Negative regulators of T-cell activation: Potential targets for therapeutic intervention in cancer, autoimmune disease, and persistent infections

Immunological Reviews

Volumn 229, Issue 1, 2009, Pages 67-87

  Pentcheva Hoang, Tsvetelina ^b   Corse, Emily ^b   Allison, James P ^a,b  

^a HOWARD HUGHES MEDICAL INSTITUTE   (United States)

^b MEMORIAL SLOAN KETTERING CANCER CENTER   (United States)

Author keywords

BTLA; CTLA 4; Immunotherapy; LAG 3; PD 1

Indexed keywords

ABATACEPT; B AND T LYMPHOCYTE ATTENUATOR; B7 ANTIGEN; CD160 ANTIGEN; CD28 ANTIGEN; CD86 ANTIGEN; CT 011; CYTOTOXIC T LYMPHOCYTE ANTIGEN 4; CYTOTOXIC T LYMPHOCYTE ANTIGEN 4 ANTIBODY; GLYCOPROTEIN; GRANULOCYTE MACROPHAGE COLONY STIMULATING FACTOR; HERPESVIRUS ENTRY MEDIATOR; INDOLEAMINE 2,3 DIOXYGENASE; PROTEIN ANTIBODY; PROTEIN B7 H3; PROTEIN B7X; PROTEIN LAG 3; PROTEIN PD 1; PROTEIN PD L1; PROTEIN PD L2; T LYMPHOCYTE RECEPTOR; UNCLASSIFIED DRUG;

ADAPTIVE IMMUNITY; AUTOIMMUNE DISEASE; AUTOIMMUNITY; B CELL LYMPHOMA; CANCER GROWTH; CELL FUNCTION; CLINICAL TRIAL; DRUG MECHANISM; DRUG POTENTIATION; HEMATOLOGIC MALIGNANCY; HUMAN; IMMUNOLOGICAL TOLERANCE; MELANOMA; NEOPLASM; NONHUMAN; OVARY CARCINOMA; PERSISTENT INFECTION; PRIORITY JOURNAL; PROSTATE ADENOCARCINOMA; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN STRUCTURE; REGULATORY T LYMPHOCYTE; REVIEW; RHEUMATOID ARTHRITIS; SIGNAL TRANSDUCTION; T CELL LYMPHOMA; T LYMPHOCYTE ACTIVATION; TRYPTOPHAN METABOLISM; VIRUS IMMUNITY;

ANIMALS; ANTIGENS, CD; ANTIGENS, CD28; AUTOIMMUNE DISEASES; HUMANS; IMMUNOTHERAPY; INFECTION; LYMPHOCYTE ACTIVATION; NEOPLASMS; RECEPTORS, ANTIGEN, T-CELL; T-LYMPHOCYTES;

EID: 65349083187     PISSN: 01052896     EISSN: 1600065X     Source Type: Journal    
DOI: 10.1111/j.1600-065X.2009.00763.x     Document Type: Review

References (260)

1. Mueller DL, Jenkins MK, Schwartz RH. Clonal expansion versus functional clonal inactivation: a costimulatory signalling pathway determines the outcome of T cell antigen receptor occupancy. Annu Rev Immunol 1989 7 : 445 480.
2. Jenkins MK, Taylor PS, Norton SD, Urdahl KB. CD28 delivers a costimulatory signal involved in antigen-specific IL-2 production by human T cells. J Immunol 1991 147 : 2461 2466.
3. Harding FA, McArthur JG, Gross JA, Raulet DH, Allison JP. CD28-mediated signalling co-stimulates murine T cells and prevents induction of anergy in T-cell clones. Nature 1992 356 : 607 609.
4. Lindsten T, June CH, Ledbetter JA, Stella G, Thompson CB. Regulation of lymphokine messenger RNA stability by a surface-mediated T cell activation pathway. Science 1989 244 : 339 343.
5. Boise LH, et al. CD28 costimulation can promote T cell survival by enhancing the expression of Bcl-XL. Immunity 1995 3 : 87 98.
6. Wulfing C, Sumen C, Sjaastad MD, Wu LC, Dustin ML, Davis MM. Costimulation and endogenous MHC ligands contribute to T cell recognition. Nat Immunol 2002 3 : 42 47.
7. Rudd CE, Raab M. Independent CD28 signaling via VAV and SLP-76: a model for in trans costimulation. Immunol Rev 2003 192 : 32 41.
8. Viola A, Schroeder S, Sakakibara Y, Lanzavecchia A. T lymphocyte costimulation mediated by reorganization of membrane microdomains. Science 1999 283 : 680 682.
9. Brunet JF, et al. A new member of the immunoglobulin superfamily - CTLA-4. Nature 1987 328 : 267 270.
10. Linsley PS, Greene JL, Brady W, Bajorath J, Ledbetter JA, Peach R. Human B7-1 (CD80) and B7-2 (CD86) bind with similar avidities but distinct kinetics to CD28 and CTLA-4 receptors. Immunity 1994 1 : 793 801.
11. Collins AV, et al. The interaction properties of costimulatory molecules revisited. Immunity 2002 17 : 201 210.
12. Walunas TL, Bakker CY, Bluestone JA. CTLA-4 ligation blocks CD28-dependent T cell activation [erratum appears in J Exp Med 1996;184:301]. J Exp Med 1996 183 : 2541 2550.
13. Krummel MF, Allison JP. CTLA-4 engagement inhibits IL-2 accumulation and cell cycle progression upon activation of resting T cells. J Exp Med 1996 183 : 2533 2540.
14. Waterhouse P, et al. Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4. Science 1995 270 : 985 988.
15. Tivol EA, Borriello F, Schweitzer AN, Lynch WP, Bluestone JA, Sharpe AH. Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity 1995 3 : 541 547.
16. Chambers CA, Cado D, Truong T, Allison JP. Thymocyte development is normal in CTLA-4-deficient mice. Proc Natl Acad Sci USA 1997 94 : 9296 9301.
17. Hutloff A, et al. ICOS is an inducible T-cell co-stimulator structurally and functionally related to CD28. Nature 1999 397 : 263 266.
18. Swallow MM, Wallin JJ, Sha WC. B7h, a novel costimulatory homolog of B7.1 and B7.2, is induced by TNFalpha. Immunity 1999 11 : 423 432.
19. Yoshinaga SK, et al. T-cell co-stimulation through B7RP-1 and ICOS. Nature 1999 402 : 827 832.
20. Ishida Y, Agata Y, Shibahara K, Honjo T. Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J 1992 11 : 3887 3895.
21. Dong H, Zhu G, Tamada K, Chen L. B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Nat Med 1999 5 : 1365 1369.
22. Freeman GJ, et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med 2000 192 : 1027 1034.
23. Latchman Y, et al. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol 2001 2 : 261 268.
24. Chapoval AI, et al. B7-H3: a costimulatory molecule for T cell activation and IFN-gamma production. Nat Immunol 2001 2 : 269 274.
25. Suh WK, et al. The B7 family member B7-H3 preferentially down-regulates T helper type 1-mediated immune responses. Nat Immunol 2003 4 : 899 906.
26. Zang X, Loke P, Kim J, Murphy K, Waitz R, Allison JP. B7x: a widely expressed B7 family member that inhibits T cell activation. Proc Natl Acad Sci USA 2003 100 : 10388 10392.
27. Prasad DV, Richards S, Mai XM, Dong C. B7S1, a novel B7 family member that negatively regulates T cell activation. Immunity 2003 18 : 863 873.
28. Sica GL, et al. B7-H4, a molecule of the B7 family, negatively regulates T cell immunity. Immunity 2003 18 : 849 861.
29. Watanabe N, et al. BTLA is a lymphocyte inhibitory receptor with similarities to CTLA-4 and PD-1. Nat Immunol 2003 4 : 670 679.
30. Sedy JR, et al. B and T lymphocyte attenuator regulates T cell activation through interaction with herpesvirus entry mediator. Nat Immunol 2005 6 : 90 98.
31. Cai G, Anumanthan A, Brown JA, Greenfield EA, Zhu B, Freeman GJ. CD160 inhibits activation of human CD4+ T cells through interaction with herpesvirus entry mediator. Nat Immunol 2008 9 : 176 185.
32. Triebel F, et al. LAG-3, a novel lymphocyte activation gene closely related to CD4. J Exp Med 1990 171 : 1393 1405.
33. Workman CJ, Cauley LS, Kim IJ, Blackman MA, Woodland DL, Vignali DA. Lymphocyte activation gene-3 (CD223) regulates the size of the expanding T cell population following antigen activation in vivo. J Immunol 2004 172 : 5450 5455.
34. Grosso JF, et al. LAG-3 regulates CD8+ T cell accumulation and effector function in murine self- and tumor-tolerance systems. J Clin Invest 2007 117 : 3383 3392.
35. Linsley PS, et al. Binding stoichiometry of the cytotoxic T lymphocyte-associated molecule-4 (CTLA-4). A disulfide-linked homodimer binds two CD86 molecules. J Biol Chem 1995 270 : 15417 15424.
36. Magistrelli G, et al. A soluble form of CTLA-4 generated by alternative splicing is expressed by nonstimulated human T cells. Eur J Immunol 1999 29 : 3596 3602.
37. Oaks MK, Hallett KM, Penwell RT, Stauber EC, Warren SJ, Tector AJ. A native soluble form of CTLA-4. Cell Immunol 2000 201 : 144 153.
38. Ueda H, et al. Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature 2003 423 : 506 511.
39. Vijayakrishnan L, et al. An autoimmune disease-associated CTLA-4 splice variant lacking the B7 binding domain signals negatively in T cells. Immunity 2004 20 : 563 575.
40. Metzler WJ, et al. Solution structure of human CTLA-4 and delineation of a CD80/CD86 binding site conserved in CD28. Nat Struct Biol 1997 4 : 527 531.
41. Ostrov DA, Shi W, Schwartz JC, Almo SC, Nathenson SG. Structure of murine CTLA-4 and its role in modulating T cell responsiveness. Science 2000 290 : 816 819.
42. Schwartz JC, Zhang X, Fedorov AA, Nathenson SG, Almo SC. Structural basis for co-stimulation by the human CTLA-4/B7-2 complex. Nature 2001 410 : 604 608.
43. Stamper CC, et al. Crystal structure of the B7-1/CTLA-4 complex that inhibits human immune responses. Nature 2001 410 : 608 611.
44. Freeman GJ, et al. Structure, expression, and T cell costimulatory activity of the murine homologue of the human B lymphocyte activation antigen B7. J Exp Med 1991 174 : 625 631.
45. Borriello F, Freeman GJ, Edelhoff S, Disteche CM, Nadler LM, Sharpe AH. Characterization of the murine B7-1 genomic locus reveals an additional exon encoding an alternative cytoplasmic domain and a chromosomal location of chromosome 16, band B5. J Immunol 1994 153 : 5038 5048.
46. Ikemizu S, et al. Structure and dimerization of a soluble form of B7-1. Immunity 2000 12 : 51 60.
47. Freeman GJ, et al. Murine B7-2, an alternative CTLA4 counter-receptor that costimulates T cell proliferation and interleukin 2 production. J Exp Med 1993 178 : 2185 2192.
48. Freeman GJ, et al. Cloning of B7-2: a CTLA-4 counter-receptor that costimulates human T cell proliferation. Science 1993 262 : 909 911.
49. Zhang X, Schwartz JC, Almo SC, Nathenson SG. Crystal structure of the receptor-binding domain of human B7-2: insights into organization and signaling. Proc Natl Acad Sci USA 2003 100 : 2586 2591.
50. Carreno BM, et al. CTLA-4 (CD152) can inhibit T cell activation by two different mechanisms depending on its level of cell surface expression. J Immunol 2000 165 : 1352 1356.
51. Bhatia S, Edidin M, Almo SC, Nathenson SG. Different cell surface oligomeric states of B7-1 and B7-2: implications for signaling. Proc Natl Acad Sci USA 2005 102 : 15569 15574.
52. Lindsten T, et al. Characterization of CTLA-4 structure and expression on human T cells. J Immunol 1993 151 : 3489 3499.
53. Perkins D, et al. Regulation of CTLA-4 expression during T cell activation. J Immunol 1996 156 : 4154 4159.
54. Leung HT, Bradshaw J, Cleaveland JS, Linsley PS. Cytotoxic T lymphocyte-associated molecule-4, a high-avidity receptor for CD80 and CD86, contains an intracellular localization motif in its cytoplasmic tail. J Biol Chem 1995 270 : 25107 25114.
55. Alegre ML, et al. Regulation of surface and intracellular expression of CTLA4 on mouse T cells. J Immunol 1996 157 : 4762 4770.
56. Linsley PS, Bradshaw J, Greene J, Peach R, Bennett KL, Mittler RS. Intracellular trafficking of CTLA-4 and focal localization towards sites of TCR engagement. Immunity 1996 4 : 535 543.
57. Iida T, et al. Regulation of cell surface expression of CTLA-4 by secretion of CTLA-4-containing lysosomes upon activation of CD4+ T cells. J Immunol 2000 165 : 5062 5068.
58. Valk E, Leung R, Kang H, Kaneko K, Rudd CE, Schneider H. T cell receptor-interacting molecule acts as a chaperone to modulate surface expression of the CTLA-4 coreceptor. Immunity 2006 25 : 807 821.
59. Shiratori T, et al. Tyrosine phosphorylation controls internalization of CTLA-4 by regulating its interaction with clathrin-associated adaptor complex AP- 2. Immunity 1997 6 : 583 589.
60. Zhang Y, Allison JP. Interaction of CTLA-4 with AP50, a clathrin-coated pit adaptor protein. Proc Natl Acad Sci USA 1997 94 : 9273 9278.
61. Chuang E, Alegre ML, Duckett CS, Noel PJ, Vander Heiden MG, Thompson CB. Interaction of CTLA-4 with the clathrin-associated protein AP50 results in ligand-independent endocytosis that limits cell surface expression. J Immunol 1997 159 : 144 151.
62. Schneider H, et al. Cytolytic T lymphocyte-associated antigen-4 and the TCR zeta/CD3 complex, but not CD28, interact with clathrin adaptor complexes AP-1 and AP-2. J Immunol 1999 163 : 1868 1879.
63. Egen JG, Allison JP. Cytotoxic T lymphocyte antigen-4 accumulation in the immunological synapse is regulated by TCR signal strength. Immunity 2002 16 : 23 35.
64. Takahashi T, et al. Immunologic self-tolerance maintained by CD25(+)CD4(+) regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4. J Exp Med 2000 192 : 303 310.
65. Read S, Malmstrom V, Powrie F. Cytotoxic T lymphocyte-associated antigen 4 plays an essential role in the function of CD25(+)CD4(+) regulatory cells that control intestinal inflammation. J Exp Med 2000 192 : 295 302.
66. Hsieh CS, Liang Y, Tyznik AJ, Self SG, Liggitt D, Rudensky AY. Recognition of the peripheral self by naturally arising CD25+ CD4+ T cell receptors. Immunity 2004 21 : 267 277.
67. Jordan MS, et al. Thymic selection of CD4+CD25+ regulatory T cells induced by an agonist self-peptide. Nat Immunol 2001 2 : 301 306.
68. Wing K, et al. CTLA-4 control over Foxp3+ regulatory T cell function. Science 2008 322 : 271 275.
69. Hathcock KS, Laszlo G, Dickler HB, Bradshaw J, Linsley P, Hodes RJ. Identification of an alternative CTLA-4 ligand costimulatory for T cell activation. Science 1993 262 : 905 907.
70. Freeman GJ, et al. Uncovering of functional alternative CTLA-4 counter-receptor in B7-deficient mice. Science 1993 262 : 907 909.
71. Borriello F, et al. B7-1 and B7-2 have overlapping, critical roles in immunoglobulin class switching and germinal center formation. Immunity 1997 6 : 303 313.
72. Hathcock KS, Laszlo G, Pucillo C, Linsley P, Hodes RJ. Comparative analysis of B7-1 and B7-2 costimulatory ligands: expression and function. J Exp Med 1994 180 : 631 640.
73. Lenschow DJ, et al. Expression and functional significance of an additional ligand for CTLA-4. Proc Natl Acad Sci USA 1993 90 : 11054 11058.
74. Inaba K, et al. The tissue distribution of the B7-2 costimulator in mice: abundant expression on dendritic cells in situ and during maturation in vitro. J Exp Med 1994 180 : 1849 1860.
75. Zheng Y, Manzotti CN, Liu M, Burke F, Mead KI, Sansom DM. CD86 and CD80 differentially modulate the suppressive function of human regulatory T cells. J Immunol 2004 172 : 2778 2784.
76. Pentcheva-Hoang T, Egen JG, Wojnoonski K, Allison JP. B7-1 and B7-2 selectively recruit CTLA-4 and CD28 to the immunological synapse. Immunity 2004 21 : 401 413.
77. Masteller EL, Chuang E, Mullen AC, Reiner SL, Thompson CB. Structural analysis of CTLA-4 function in vivo. J Immunol 2000 164 : 5319 5327.
78. Engelhardt JJ, Sullivan TJ, Allison JP. CTLA-4 overexpression inhibits T cell responses through a CD28-B7-dependent mechanism. J Immunol 2006 177 : 1052 1061.
79. Darlington PJ, Kirchhof MG, Criado G, Sondhi J, Madrenas J. Hierarchical regulation of CTLA-4 dimer-based lattice formation and its biological relevance for T cell inactivation. J Immunol 2005 175 : 996 1004.
80. Walunas TL, et al. CTLA-4 can function as a negative regulator of T cell activation. Immunity 1994 1 : 405 413.
81. Fallarino F, Fields PE, Gajewski TF. B7-1 engagement of cytotoxic T lymphocyte antigen 4 inhibits T cell activation in the absence of CD28. J Exp Med 1998 188 : 205 210.
82. Lin H, Rathmell JC, Gray GS, Thompson CB, Leiden JM, Alegre ML. Cytotoxic T lymphocyte antigen 4 (CTLA4) blockade accelerates the acute rejection of cardiac allografts in CD28-deficient mice: CTLA4 can function independently of CD28. J Exp Med 1998 188 : 199 204.
83. Dariavach P, Mattei MG, Golstein P, Lefranc MP. Human Ig superfamily CTLA-4 gene: chromosomal localization and identity of protein sequence between murine and human CTLA-4 cytoplasmic domains. Eur J Immunol 1988 18 : 1901 1905.
84. Marengere LE, Waterhouse P, Duncan GS, Mittrucker HW, Feng GS, Mak TW. Regulation of T cell receptor signaling by tyrosine phosphatase SYP association with CTLA-4. Science 1996 272 : 1170 1173.
85. Lee KM, et al. Molecular basis of T cell inactivation by CTLA-4. Science 1998 282 : 2263 2266.
86. Chuang E, et al. The CD28 and CTLA-4 receptors associate with the serine/threonine phosphatase PP2A. Immunity 2000 13 : 313 322.
87. Baroja ML, et al. Inhibition of CTLA-4 function by the regulatory subunit of serine/threonine phosphatase 2A. J Immunol 2002 168 : 5070 5078.
88. Martin M, Schneider H, Azouz A, Rudd CE. Cytotoxic T lymphocyte antigen 4 and CD28 modulate cell surface raft expression in their regulation of T cell function. J Exp Med 2001 194 : 1675 1681.
89. Xavier R, Brennan T, Li Q, McCormack C, Seed B. Membrane compartmentation is required for efficient T cell activation. Immunity 1998 8 : 723 732.
90. Darlington PJ, et al. Surface cytotoxic T lymphocyte-associated antigen 4 partitions within lipid rafts and relocates to the immunological synapse under conditions of inhibition of T cell activation. J Exp Med 2002 195 : 1337 1347.
91. Chikuma S, Imboden JB, Bluestone JA. Negative regulation of T cell receptor-lipid raft interaction by cytotoxic T lymphocyte-associated antigen 4. J Exp Med 2003 197 : 129 135.
92. Chikuma S, Abbas AK, Bluestone JA. B7-independent inhibition of T cells by CTLA-4. J Immunol 2005 175 : 177 181.
93. Schneider H, et al. Reversal of the TCR stop signal by CTLA-4. Science 2006 313 : 1972 1975.
94. Tang Q, et al. Visualizing regulatory T cell control of autoimmune responses in nonobese diabetic mice. Nat Immunol 2006 7 : 83 92.
95. Tadokoro CE, et al. Regulatory T cells inhibit stable contacts between CD4+ T cells and dendritic cells in vivo. J Exp Med 2006 203 : 505 511.
96. Schneider H, Smith X, Liu H, Bismuth G, Rudd CE. CTLA-4 disrupts ZAP70 microcluster formation with reduced T cell/APC dwell times and calcium mobilization. Eur J Immunol 2008 38 : 40 47.
97. Bachmann MF, Kohler G, Ecabert B, Mak TW, Kopf M. Cutting edge: lymphoproliferative disease in the absence of CTLA-4 is not T cell autonomous. J Immunol 1999 163 : 1128 1131.
98. Tang Q, Boden EK, Henriksen KJ, Bour-Jordan H, Bi M, Bluestone JA. Distinct roles of CTLA-4 and TGF-beta in CD4+CD25+ regulatory T cell function. Eur J Immunol 2004 34 : 2996 3005.
99. Read S, et al. Blockade of CTLA-4 on CD4+CD25+ regulatory T cells abrogates their function in vivo. J Immunol 2006 177 : 4376 4383.
100. Munn DH, et al. Prevention of allogeneic fetal rejection by tryptophan catabolism. Science 1998 281 : 1191 1193.
101. Grohmann U, et al. CTLA-4-Ig regulates tryptophan catabolism in vivo. Nat Immunol 2002 3 : 1097 1101.
102. Munn DH, et al. Potential regulatory function of human dendritic cells expressing indoleamine 2,3-dioxygenase. Science 2002 297 : 1867 1870.
103. Asseman C, Mauze S, Leach MW, Coffman RL, Powrie F. An essential role for interleukin 10 in the function of regulatory T cells that inhibit intestinal inflammation. J Exp Med 1999 190 : 995 1004.
104. Fallarino F, et al. Modulation of tryptophan catabolism by regulatory T cells. Nat Immunol 2003 4 : 1206 1212.
105. Judge TA, Wu Z, Zheng XG, Sharpe AH, Sayegh MH, Turka LA. The role of CD80, CD86, and CTLA4 in alloimmune responses and the induction of long-term allograft survival. J Immunol 1999 162 : 1947 1951.
106. Zheng XX, et al. The role of donor and recipient B7-1 (CD80) in allograft rejection. J Immunol 1997 159 : 1169 1173.
107. Paust S, Lu L, McCarty N, Cantor H. Engagement of B7 on effector T cells by regulatory T cells prevents autoimmune disease. Proc Natl Acad Sci USA 2004 101 : 10398 10403.
108. Linsley PS, Brady W, Urnes M, Grosmaire LS, Damle NK, Ledbetter JA. CTLA-4 is a second receptor for the B cell activation antigen B7. J Exp Med 1991 174 : 561 569.
109. Finck BK, Linsley PS, Wofsy D. Treatment of murine lupus with CTLA4Ig. Science 1994 265 : 1225 1227.
110. Lenschow DJ, et al. Long-term survival of xenogeneic pancreatic islet grafts induced by CTLA4lg. Science 1992 257 : 789 792.
111. Linsley PS, et al. Immunosuppression in vivo by a soluble form of the CTLA-4 T cell activation molecule. Science 1992 257 : 792 795.
112. Tivol EA, et al. CTLA4Ig prevents lymphoproliferation and fatal multiorgan tissue destruction in CTLA-4-deficient mice. J Immunol 1997 158 : 5091 5094.
113. Mandelbrot DA, McAdam AJ, Sharpe AH. B7-1 or B7-2 is required to produce the lymphoproliferative phenotype in mice lacking cytotoxic T lymphocyte-associated antigen 4 (CTLA-4). J Exp Med 1999 189 : 435 440.
114. Reynolds J, Shojania K, Marra CA. Abatacept: a novel treatment for moderate-to-severe rheumatoid arthritis. Pharmacotherapy 2007 27 : 1693 1701.
115. Leach DR, Krummel MF, Allison JP. Enhancement of antitumor immunity by CTLA-4 blockade. Science 1996 271 : 1734 1736.
116. Kwon ED, et al. Manipulation of T cell costimulatory and inhibitory signals for immunotherapy of prostate cancer. Proc Natl Acad Sci USA 1997 94 : 8099 8103.
117. Yang YF, et al. Enhanced induction of antitumor T-cell responses by cytotoxic T lymphocyte-associated molecule-4 blockade: the effect is manifested only at the restricted tumor-bearing stages. Cancer Res 1997 57 : 4036 4041.
118. Shrikant P, Khoruts A, Mescher MF. CTLA-4 blockade reverses CD8+ T cell tolerance to tumor by a CD4+ T cell- and IL-2-dependent mechanism. Immunity 1999 11 : 483 493.
119. Sotomayor EM, Borrello I, Tubb E, Allison JP, Levitsky HI. In vivo blockade of CTLA-4 enhances the priming of responsive T cells but fails to prevent the induction of tumor antigen-specific tolerance. Proc Natl Acad Sci USA 1999 96 : 11476 11481.
120. van Elsas A, Hurwitz AA, Allison JP. Combination immunotherapy of B16 melanoma using anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and granulocyte/macrophage colony-stimulating factor (GM-CSF)-producing vaccines induces rejection of subcutaneous and metastatic tumors accompanied by autoimmune depigmentation. J Exp Med 1999 190 : 355 366.
121. Hurwitz AA, Yu TF, Leach DR, Allison JP. CTLA-4 blockade synergizes with tumor-derived granulocyte-macrophage colony-stimulating factor for treatment of an experimental mammary carcinoma. Proc Natl Acad Sci USA 1998 95 : 10067 10071.
122. Hurwitz AA, et al. Combination immunotherapy of primary prostate cancer in a transgenic mouse model using CTLA-4 blockade. Cancer Res 2000 60 : 2444 2448.
123. Quezada SA, Peggs KS, Curran MA, Allison JP. CTLA4 blockade and GM-CSF combination immunotherapy alters the intratumor balance of effector and regulatory T cells. J Clin Invest 2006 116 : 1935 1945.
124. Quezada SA, Peggs KS, Simpson TR, Shen Y, Littman DR, Allison JP. Limited tumor infiltration by activated T effector cells restricts the therapeutic activity of regulatory T cell depletion against established melanoma. J Exp Med 2008 205 : 2125 2138.
125. Peggs KS, Quezada SA, Allison JP. Cell intrinsic mechanisms of T-cell inhibition and application to cancer therapy. Immunol Rev 2008 224 : 141 165.
126. Shinohara T, Taniwaki M, Ishida Y, Kawaichi M, Honjo T. Structure and chromosomal localization of the human PD-1 gene (PDCD1). Genomics 1994 23 : 704 706.
127. Shlapatska LM, et al. CD150 association with either the SH2-containing inositol phosphatase or the SH2-containing protein tyrosine phosphatase is regulated by the adaptor protein SH2D1A. J Immunol 2001 166 : 5480 5487.
128. Zhang X, et al. Structural and functional analysis of the costimulatory receptor programmed death-1. Immunity 2004 20 : 337 347.
129. Wan B, et al. Aberrant regulation of synovial T cell activation by soluble costimulatory molecules in rheumatoid arthritis. J Immunol 2006 177 : 8844 8850.
130. Nielsen C, Ohm-Laursen L, Barington T, Husby S, Lillevang ST. Alternative splice variants of the human PD-1 gene. Cell Immunol 2005 235 : 109 116.
131. Lin DY, et al. The PD-1/PD-L1 complex resembles the antigen-binding Fv domains of antibodies and T cell receptors. Proc Natl Acad Sci USA 2008 105 : 3011 3016.
132. Lazar-Molnar E, Yan Q, Cao E, Ramagopal U, Nathenson SG, Almo SC. Crystal structure of the complex between programmed death-1 (PD-1) and its ligand PD-L2. Proc Natl Acad Sci USA 2008 105 : 10483 10488.
133. Agata Y, et al. Expression of the PD-1 antigen on the surface of stimulated mouse T and B lymphocytes. Int Immunol 1996 8 : 765 772.
134. Kinter AL, et al. The common γ-chain cytokines IL-2, IL-7, IL-15, and IL-21 induce the expression of programmed death-1 and its ligands. J Immunol 2008 181 : 6738 6746.
135. Raimondi G, Shufesky WJ, Tokita D, Morelli AE, Thomson AW. Regulated compartmentalization of programmed cell death-1 discriminates CD4+CD25+ resting regulatory T cells from activated T cells. J Immunol 2006 176 : 2808 2816.
136. Pentcheva-Hoang T, Chen L, Pardoll DM, Allison JP. Programmed death-1 concentration at the immunological synapse is determined by ligand affinity and availability. Proc Natl Acad Sci USA 2007 104 : 17765 17770.
137. Barber DL, et al. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature 2006 439 : 682 687.
138. Day CL, et al. PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature 2006 443 : 350 354.
139. Petrovas C, et al. PD-1 is a regulator of virus-specific CD8+ T cell survival in HIV infection. J Exp Med 2006 203 : 2281 2292.
140. Trautmann L, et al. Upregulation of PD-1 expression on HIV-specific CD8+ T cells leads to reversible immune dysfunction [erratum appears in Nat Med 2006;12:1329]. Nat Med 2006 12 : 1198 1202.
141. Ishida M, et al. Differential expression of PD-L1 and PD-L2, ligands for an inhibitory receptor PD-1, in the cells of lymphohematopoietic tissues. Immunol Lett 2002 84 : 57 62.
142. Yamazaki T, et al. Expression of programmed death 1 ligands by murine T cells and APC. J Immunol 2002 169 : 5538 5545.
143. Liang SC, et al. Regulation of PD-1, PD-L1, and PD-L2 expression during normal and autoimmune responses. Eur J Immunol 2003 33 : 2706 2716.
144. Loke P, Allison JP. PD-L1 and PD-L2 are differentially regulated by Th1 and Th2 cells. Proc Natl Acad Sci USA 2003 100 : 5336 5341.
145. Nakae S, et al. Mast cells enhance T cell activation: importance of mast cell costimulatory molecules and secreted TNF. J Immunol 2006 176 : 2238 2248.
146. Zhong X, Tumang JR, Gao W, Bai C, Rothstein TL. PD-L2 expression extends beyond dendritic cells/macrophages to B1 cells enriched for V(H)11/V(H)12 and phosphatidylcholine binding. Eur J Immunol 2007 37 : 2405 2410.
147. Okazaki T, Maeda A, Nishimura H, Kurosaki T, Honjo T. PD-1 immunoreceptor inhibits B cell receptor-mediated signaling by recruiting src homology 2-domain-containing tyrosine phosphatase 2 to phosphotyrosine. Proc Natl Acad Sci USA 2001 98 : 13866 13871.
148. Chemnitz JM, Parry RV, Nichols KE, June CH, Riley JL. SHP-1 and SHP-2 associate with immunoreceptor tyrosine-based switch motif of programmed death 1 upon primary human T cell stimulation, but only receptor ligation prevents T cell activation. J Immunol 2004 173 : 945 954.
149. Parry RV, et al. CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol Cell Biol 2005 25 : 9543 9553.
150. Sheppard KA, et al. PD-1 inhibits T-cell receptor induced phosphorylation of the ZAP70/CD3zeta signalosome and downstream signaling to PKCtheta. FEBS Lett 2004 574 : 37 41.
151. Butte MJ, Keir ME, Phamduy TB, Sharpe AH, Freeman GJ. Programmed death-1 ligand 1 interacts specifically with the B7-1 costimulatory molecule to inhibit T cell responses. Immunity 2007 27 : 111 122.
152. Butte MJ, Pena-Cruz V, Kim MJ, Freeman GJ, Sharpe AH. Interaction of human PD-L1 and B7-1. Mol Immunol 2008 45 : 3567 3572.
153. Nishimura H, Nose M, Hiai H, Minato N, Honjo T. Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity 1999 11 : 141 151.
154. Nishimura H, et al. Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice. Science 2001 291 : 319 322.
155. Okazaki T, et al. Autoantibodies against cardiac troponin I are responsible for dilated cardiomyopathy in PD-1-deficient mice. Nat Med 2003 9 : 1477 1483.
156. Wang J, Yoshida T, Nakaki F, Hiai H, Okazaki T, Honjo T. Establishment of NOD-Pdcd1-/- mice as an efficient animal model of type I diabetes. Proc Natl Acad Sci USA 2005 102 : 11823 11828.
157. Latchman YE, et al. PD-L1-deficient mice show that PD-L1 on T cells, antigen-presenting cells, and host tissues negatively regulates T cells. Proc Natl Acad Sci USA 2004 101 : 10691 10696.
158. Dong H, Zhu G, Tamada K, Flies DB, van Deursen JM, Chen L. B7-H1 determines accumulation and deletion of intrahepatic CD8(+) T lymphocytes. Immunity 2004 20 : 327 336.
159. Shin T, et al. In vivo costimulatory role of B7-DC in tuning T helper cell 1 and cytotoxic T lymphocyte responses. J Exp Med 2005 201 : 1531 1541.
160. Zhang Y, et al. Regulation of T cell activation and tolerance by PDL2. Proc Natl Acad Sci USA 2006 103 : 11695 11700.
161. Salama AD, et al. Critical role of the programmed death-1 (PD-1) pathway in regulation of experimental autoimmune encephalomyelitis. J Exp Med 2003 198 : 71 78.
162. Zhu B, et al. Differential role of programmed death-ligand 1 [corrected] and programmed death-ligand 2 [corrected] in regulating the susceptibility and chronic progression of experimental autoimmune encephalomyelitis [erratum appears in J Immunol 2006;176:5683]. J Immunol 2006 176 : 3480 3489.
163. Carter LL, et al. PD-1/PD-L1, but not PD-1/PD-L2, interactions regulate the severity of experimental autoimmune encephalomyelitis. J Neuroimmunol 2007 182 : 124 134.
164. Ansari MJ, et al. The programmed death-1 (PD-1) pathway regulates autoimmune diabetes in nonobese diabetic (NOD) mice. J Exp Med 2003 198 : 63 69.
165. Keir ME, et al. Tissue expression of PD-L1 mediates peripheral T cell tolerance. J Exp Med 2006 203 : 883 895.
166. Keir ME, Freeman GJ, Sharpe AH. PD-1 regulates self-reactive CD8+ T cell responses to antigen in lymph nodes and tissues. J Immunol 2007 179 : 5064 5070.
167. Fife BT, et al. Insulin-induced remission in new-onset NOD mice is maintained by the PD-1-PD-L1 pathway. J Exp Med 2006 203 : 2737 2747.
168. Subudhi SK, et al. Local expression of B7-H1 promotes organ-specific autoimmunity and transplant rejection. J Clin Invest 2004 113 : 694 700.
169. Guleria I, et al. A critical role for the programmed death ligand 1 in fetomaternal tolerance. J Exp Med 2005 202 : 231 237.
170. Sandner SE, et al. Role of the programmed death-1 pathway in regulation of alloimmune responses in vivo. J Immunol 2005 174 : 3408 3415.
171. Ito T, et al. Analysis of the role of negative T cell costimulatory pathways in CD4 and CD8 T cell-mediated alloimmune responses in vivo. J Immunol 2005 174 : 6648 6656.
172. Seo SK, et al. Co-inhibitory role of T-cell-associated B7-H1 and B7-DC in the T-cell immune response. Immunol Lett 2006 102 : 222 228.
173. Blazar BR, et al. Blockade of programmed death-1 engagement accelerates graft-versus-host disease lethality by an IFN-gamma-dependent mechanism. J Immunol 2003 171 : 1272 1277.
174. Matsumoto K, et al. B7-DC regulates asthmatic response by an IFN-gamma-dependent mechanism. J Immunol 2004 172 : 2530 2541.
175. Oflazoglu E, et al. Paradoxical role of programmed death-1 ligand 2 in Th2 immune responses in vitro and in a mouse asthma model in vivo. Eur J Immunol 2004 34 : 3326 3336.
176. Fukushima A, Yamaguchi T, Azuma M, Yagita H, Ueno H. Involvement of programmed death-ligand 2 (PD-L2) in the development of experimental allergic conjunctivitis in mice. Br J Ophthalmol 2006 90 : 1040 1045.
177. Dong H, et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion [erratum appears in Nat Med 2002;8:1039]. Nat Med 2002 8 : 793 800.
178. Iwai Y, Ishida M, Tanaka Y, Okazaki T, Honjo T, Minato N. Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proc Natl Acad Sci USA 2002 99 : 12293 12297.
179. Hamanishi J, et al. Programmed cell death 1 ligand 1 and tumor-infiltrating CD8+ T lymphocytes are prognostic factors of human ovarian cancer. Proc Natl Acad Sci USA 2007 104 : 3360 3365.
180. Thompson RH, et al. Costimulatory B7-H1 in renal cell carcinoma patients: indicator of tumor aggressiveness and potential therapeutic target. Proc Natl Acad Sci USA 2004 101 : 17174 17179.
181. Thompson RH, et al. Costimulatory molecule B7-H1 in primary and metastatic clear cell renal cell carcinoma. Cancer 2005 104 : 2084 2091.
182. Thompson RH, et al. Tumor B7-H1 is associated with poor prognosis in renal cell carcinoma patients with long-term follow-up. Cancer Res 2006 66 : 3381 3385.
183. Inman BA, et al. PD-L1 (B7-H1) expression by urothelial carcinoma of the bladder and BCG-induced granulomata: associations with localized stage progression. Cancer 2007 109 : 1499 1505.
184. Nakanishi J, Wada Y, Matsumoto K, Azuma M, Kikuchi K, Ueda S. Overexpression of B7-H1 (PD-L1) significantly associates with tumor grade and postoperative prognosis in human urothelial cancers. Cancer Immunol Immunother 2007 56 : 1173 1182.
185. Nomi T, et al. Clinical significance and therapeutic potential of the programmed death-1 ligand/programmed death-1 pathway in human pancreatic cancer. Clin Cancer Res 2007 13 : 2151 2157.
186. Konishi J, Yamazaki K, Azuma M, Kinoshita I, Dosaka-Akita H, Nishimura M. B7-H1 expression on non-small cell lung cancer cells and its relationship with tumor-infiltrating lymphocytes and their PD-1 expression. Clin Cancer Res 2004 10 : 5094 5100.
187. Wu C, Zhu Y, Jiang J, Zhao J, Zhang XG, Xu N. Immunohistochemical localization of programmed death-1 ligand-1 (PD-L1) in gastric carcinoma and its clinical significance. Acta Histochem 2006 108 : 19 24.
188. Azuma T, Yao S, Zhu G, Flies AS, Flies SJ, Chen L. B7-H1 is a ubiquitous antiapoptotic receptor on cancer cells. Blood 2008 111 : 3635 3643.
189. Liu X, et al. B7DC/PDL2 promotes tumor immunity by a PD-1-independent mechanism. J Exp Med 2003 197 : 1721 1730.
190. Tseng SY, et al. B7-DC, a new dendritic cell molecule with potent costimulatory properties for T cells. J Exp Med 2001 193 : 839 846.
191. Tamura H, et al. B7-H1 costimulation preferentially enhances CD28-independent T-helper cell function. Blood 2001 97 : 1809 1816.
192. Curiel TJ, et al. Blockade of B7-H1 improves myeloid dendritic
193. Strome SE, et al. B7-H1 blockade augments adoptive T-cell immunotherapy for squamous cell carcinoma. Cancer Res 2003 63 : 6501 6505.
194. Hirano F, et al. Blockade of B7-H1 and PD-1 by monoclonal antibodies potentiates cancer therapeutic immunity. Cancer Res 2005 65 : 1089 1096.
195. Berger R, et al. Phase I safety and pharmacokinetic study of CT-011, a humanized antibody interacting with PD-1, in patients with advanced hematologic malignancies. Clin Cancer Res 2008 14 : 3044 3051.
196. Boni C, et al. Characterization of hepatitis B virus (HBV)-specific T-cell dysfunction in chronic HBV infection. J Virol 2007 81 : 4215 4225.
197. Urbani S, et al. PD-1 expression in acute hepatitis C virus (HCV) infection is associated with HCV-specific CD8 exhaustion. J Virol 2006 80 : 11398 11403.
198. Penna A, et al. Dysfunction and functional restoration of HCV-specific CD8 responses in chronic hepatitis C virus infection. Hepatology 2007 45 : 588 601.
199. Radziewicz H, et al. Liver-infiltrating lymphocytes in chronic human hepatitis C virus infection display an exhausted phenotype with high levels of PD-1 and low levels of CD127 expression. J Virol 2007 81 : 2545 2553.
200. Jeong HY, et al. Blocking of monocyte-associated B7-H1 (CD274) enhances HCV-specific T cell immunity in chronic hepatitis C infection. J Leukoc Biol 2008 83 : 755 764.
201. Jun H, et al. B7-H1 (CD274) inhibits the development of herpetic stromal keratitis (HSK). FEBS Lett 2005 579 : 6259 6264.
202. Das S, Suarez G, Beswick EJ, Sierra JC, Graham DY, Reyes VE. Expression of B7-H1 on gastric epithelial cells: its potential role in regulating T cells during Helicobacter pylori infection. J Immunol 2006 176 : 3000 3009.
203. Jurado JO, et al. Programmed death (PD)-1:PD-ligand 1/PD-ligand 2 pathway inhibits T cell effector functions during human tuberculosis. J Immunol 2008 181 : 116 125.
204. Hashiguchi M, Kobori H, Ritprajak P, Kamimura Y, Kozono H, Azuma M. Triggering receptor expressed on myeloid cell-like transcript 2 (TLT-2) is a counter-receptor for B7-H3 and enhances T cell responses. Proc Natl Acad Sci USA 2008 105 : 10495 10500.
205. Sun M, Richards S, Prasad DV, Mai XM, Rudensky A, Dong C. Characterization of mouse and human B7-H3 genes. J Immunol 2002 168 : 6294 6297.
206. Ling V, et al. Duplication of primate and rodent B7-H3 immunoglobulin V- and C-like domains: divergent history of functional redundancy and exon loss. Genomics 2003 82 : 365 377.
207. Steinberger P, et al. Molecular characterization of human 4Ig-B7-H3, a member of the B7 family with four Ig-like domains. J Immunol 2004 172 : 2352 2359.
208. Castriconi R, et al. Identification of 4Ig-B7-H3 as a neuroblastoma-associated molecule that exerts a protective role from an NK cell-mediated lysis. Proc Natl Acad Sci USA 2004 101 : 12640 12645.
209. Choi IH, et al. Genomic organization and expression analysis of B7-H4, an immune inhibitory molecule of the B7 family. J Immunol 2003 171 : 4650 4654.
210. Kryczek I, et al. B7-H4 expression identifies a novel suppressive macrophage population in human ovarian carcinoma. J Exp Med 2006 203 : 871 881.
211. Kryczek I, et al. Cutting edge: induction of B7-H4 on APCs through IL-10: novel suppressive mode for regulatory T cells. J Immunol 2006 177 : 40 44.
212. Mirza N, Gabrilovich D. Comment on "Cutting edge: induction of B7-H4 on APCs through IL-10: novel suppressive mode for regulatory T cells". J Immunol 2007 178 : 4705 4706.
213. Suh WK, et al. Generation and characterization of B7-H4/B7S1/B7x- deficient mice. Mol Cell Biol 2006 26 : 6403 6411.
214. Luo L, et al. B7-H3 enhances tumor immunity in vivo by costimulating rapid clonal expansion of antigen-specific CD8+ cytolytic T cells. J Immunol 2004 173 : 5445 5450.
215. Sun Y, et al. B7-H3 and B7-H4 expression in non-small-cell lung cancer. Lung Cancer 2006 53 : 143 151.
216. Roth TJ, et al. B7-H3 ligand expression by prostate cancer: a novel marker of prognosis and potential target for therapy. Cancer Res 2007 67 : 7893 7900.
217. Zang X, et al. B7-H3 and B7x are highly expressed in human prostate cancer and associated with disease spread and poor outcome. Proc Natl Acad Sci USA 2007 104 : 19458 19463.
218. Krambeck AE, et al. B7-H4 expression in renal cell carcinoma and tumor vasculature: associations with cancer progression and survival. Proc Natl Acad Sci USA 2006 103 : 10391 10396.
219. Crispen PL, et al. Tumor cell and tumor vasculature expression of B7-H3 predict survival in clear cell renal cell carcinoma. Clin Cancer Res 2008 14 : 5150 5157.
220. Thompson RH, et al. Serum-soluble B7x is elevated in renal cell carcinoma patients and is associated with advanced stage. Cancer Res 2008 68 : 6054 6058.
221. Tringler B, et al. B7-h4 is highly expressed in ductal and lobular breast cancer. Clin Cancer Res 2005 11 : 1842 1848.
222. Simon I, et al. B7-h4 is a novel membrane-bound protein and a candidate serum and tissue biomarker for ovarian cancer. Cancer Res 2006 66 : 1570 1575.
223. Han P, Goularte OD, Rufner K, Wilkinson B, Kaye J. An inhibitory Ig superfamily protein expressed by lymphocytes and APCs is also an early marker of thymocyte positive selection. J Immunol 2004 172 : 5931 5939.
224. Compaan DM, Gonzalez LC, Tom I, Loyet KM, Eaton D, Hymowitz SG. Attenuating lymphocyte activity: the crystal structure of the BTLA-HVEM complex. J Biol Chem 2005 280 : 39553 39561.
225. Nelson CA, et al. Structural determinants of herpesvirus entry mediator recognition by murine B and T lymphocyte attenuator. J Immunol 2008 180 : 940 947.
226. Gonzalez LC, et al. A coreceptor interaction between the CD28 and TNF receptor family members B and T lymphocyte attenuator and herpesvirus entry mediator. Proc Natl Acad Sci USA 2005 102 : 1116 1121.
227. Murphy KM, Nelson CA, Sedy JR. Balancing co-stimulation and inhibition with BTLA and HVEM. Nat Rev Immunol 2006 6 : 671 681.
228. Sedy JR, Spear PG, Ware CF. Cross-regulation between herpesviruses and the TNF superfamily members. Nat Rev Immunol 2008 8 : 861 873.
229. Ware CF. Targeting lymphocyte activation through the lymphotoxin and LIGHT pathways. Immunol Rev 2008 223 : 186 201.
230. Wang Y, et al. The role of herpesvirus entry mediator as a negative regulator of T cell-mediated responses. J Clin Invest 2005 115 : 711 717.
231. Sarrias MR, et al. The three HveA receptor ligands, gD, LT-alpha and LIGHT bind to distinct sites on HveA. Mol Immunol 2000 37 : 665 673.
232. Hurchla MA, Sedy JR, Gavrieli M, Drake CG, Murphy TL, Murphy KM. B and T lymphocyte attenuator exhibits structural and expression polymorphisms and is highly induced in anergic CD4+ T cells. J Immunol 2005 174 : 3377 3385.
233. Morel Y, et al. Reciprocal expression of the TNF family receptor herpes virus entry mediator and its ligand LIGHT on activated T cells: LIGHT down-regulates its own receptor. J Immunol 2000 165 : 4397 4404.
234. Krieg C, Han P, Stone R, Goularte OD, Kaye J. Functional analysis of B and T lymphocyte attenuator engagement on CD4+ and CD8+ T cells. J Immunol 2005 175 : 6420 6427.
235. Gavrieli M, Murphy KM. Association of Grb-2 and PI3K p85 with phosphotyrosile peptides derived from BTLA. Biochem Biophys Res Commun 2006 345 : 1440 1445.
236. Gavrieli M, Watanabe N, Loftin SK, Murphy TL, Murphy KM. Characterization of phosphotyrosine binding motifs in the cytoplasmic domain of B and T lymphocyte attenuator required for association with protein tyrosine phosphatases SHP-1 and SHP-2. Biochem Biophys Res Commun 2003 312 : 1236 1243.
237. Chemnitz JM, Lanfranco AR, Braunstein I, Riley JL. B and T lymphocyte attenuator-mediated signal transduction provides a potent inhibitory signal to primary human CD4 T cells that can be initiated by multiple phosphotyrosine motifs. J Immunol 2006 176 : 6603 6614.
238. Deppong C, et al. Cutting edge: B and T lymphocyte attenuator and programmed death receptor-1 inhibitory receptors are required for termination of acute allergic airway inflammation. J Immunol 2006 176 : 3909 3913.
239. Tao R, et al. Differential effects of B and T lymphocyte attenuator and programmed death-1 on acceptance of partially versus fully MHC-mismatched cardiac allografts. J Immunol 2005 175 : 5774 5782.
240. Tao R, Wang L, Murphy KM, Fraser CC, Hancock WW. Regulatory T cell expression of herpesvirus entry mediator suppresses the function of B and T lymphocyte attenuator-positive effector T cells. J Immunol 2008 180 : 6649 6655.
241. Truong W, et al. Negative and positive co-signaling with anti-BTLA (PJ196) and CTLA4Ig prolongs islet allograft survival. Transplantation 2007 84 : 1368 1372.
242. Truong W, et al. Combined coinhibitory and costimulatory modulation with anti-BTLA and CTLA4Ig facilitates tolerance in murine islet allografts. Am J Transplant 2007 7 : 2663 2674.
243. Oya Y, et al. Development of autoimmune hepatitis-like disease and production of autoantibodies to nuclear antigens in mice lacking B and T lymphocyte attenuator. Arthritis Rheum 2008 58 : 2498 2510.
244. Steinberg MW, et al. A crucial role for HVEM and BTLA in preventing intestinal inflammation. J Exp Med 2008 205 : 1463 1476.
245. Krieg C, Boyman O, Fu YX, Kaye J. B and T lymphocyte attenuator regulates CD8+ T cell-intrinsic homeostasis and memory cell generation. Nat Immunol 2007 8 : 162 171.
246. Deppong C, Degnan JM, Murphy TL, Murphy KM, Green JM. B and T lymphocyte attenuator regulates T cell survival in the lung. J Immunol 2008 181 : 2973 2979.
247. Kisielow M, Kisielow J, Capoferri-Sollami G, Karjalainen K. Expression of lymphocyte activation gene 3 (LAG-3) on B cells is induced by T cells. Eur J Immunol 2005 35 : 2081 2088.
248. Huard B, Prigent P, Pages F, Bruniquel D, Triebel F. T cell major histocompatibility complex class II molecules down-regulate CD4+ T cell clone responses following LAG-3 binding. Eur J Immunol 1996 26 : 1180 1186.
249. Huard B, Prigent P, Tournier M, Bruniquel D, Triebel F. CD4/major histocompatibility complex class II interaction analyzed with CD4- and lymphocyte activation gene-3 (LAG-3)-Ig fusion proteins. Eur J Immunol 1995 25 : 2718 2721.
250. Workman CJ, Rice DS, Dugger KJ, Kurschner C, Vignali DA. Phenotypic analysis of the murine CD4-related glycoprotein, CD223 (LAG-3). Eur J Immunol 2002 32 : 2255 2263.
251. Avice MN, Sarfati M, Triebel F, Delespesse G, Demeure CE. Lymphocyte activation gene-3, a MHC class II ligand expressed on activated T cells, stimulates TNF-alpha and IL-12 production by monocytes and dendritic cells. J Immunol 1999 162 : 2748 2753.
252. Miyazaki T, Dierich A, Benoist C, Mathis D. Independent modes of natural killing distinguished in mice lacking Lag3. Science 1996 272 : 405 408.
253. Workman CJ, Vignali DA. The CD4-related molecule, LAG-3 (CD223), regulates the expansion of activated T cells. Eur J Immunol 2003 33 : 970 979.
254. Workman CJ, Vignali DA. Negative regulation of T cell homeostasis by lymphocyte activation gene-3 (CD223). J Immunol 2005 174 : 688 695.
255. Workman CJ, Dugger KJ, Vignali DA. Cutting edge: molecular analysis of the negative regulatory function of lymphocyte activation gene-3. J Immunol 2002 169 : 5392 5395.
256. Macon-Lemaitre L, Triebel F. The negative regulatory function of the lymphocyte-activation gene-3 co-receptor (CD223) on human T cells. Immunology 2005 115 : 170 178.
257. Huang CT, et al. Role of LAG-3 in regulatory T cells. Immunity 2004 21 : 503 513.
258. Drake CG, et al. Androgen ablation mitigates tolerance to a prostate/prostate cancer-restricted antigen. Cancer Cell 2005 7 : 239 249.
259. Demeure CE, Wolfers J, Martin-Garcia N, Gaulard P, Triebel F. T Lymphocytes infiltrating various tumour types express the MHC class II ligand lymphocyte activation gene-3 (LAG-3): role of LAG-3/MHC class II interactions in cell-cell contacts. Eur J Cancer 2001 37 : 1709 1718.
260. Gandhi MK, et al. Expression of LAG-3 by tumor-infiltrating lymphocytes is coincident with the suppression of latent membrane antigen-specific CD8+ T-cell function in Hodgkin lymphoma patients. Blood 2006 108 : 2280 2289.