Molecular pathways regulating CD4+ T cell differentiation, anergy and memory with implications for vaccines

Trends in Molecular Medicine

Volumn 16, Issue 10, 2010, Pages 478-491

  Ahlers, Jeffrey D ^a   Belyakov, Igor M ^b  

^a NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES   (United States)

^b MIDWEST RESEARCH INSTITUTE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CD4 ANTIGEN; CD8 ANTIGEN; CHEMOKINE; CXCL11 CHEMOKINE; CXCL9 CHEMOKINE; CYCLOOXYGENASE 2; CYTOKINE; GAMMA INTERFERON INDUCIBLE PROTEIN 10; IMMUNOGLOBULIN CLASS; INTERLEUKIN 10; INTERLEUKIN 12P40; INTERLEUKIN 12P70; INTERLEUKIN 13; INTERLEUKIN 21; INTERLEUKIN 22; INTERLEUKIN 23; INTERLEUKIN 26; INTERLEUKIN 4; INTERLEUKIN 5; INTERLEUKIN 6; STAT1 PROTEIN; STAT5 PROTEIN; TOLL LIKE RECEPTOR 2; TOLL LIKE RECEPTOR 3; TOLL LIKE RECEPTOR 6; TOLL LIKE RECEPTOR 9; TRANSCRIPTION FACTOR FOXP3; TUMOR NECROSIS FACTOR ALPHA; UNINDEXED DRUG; VACCINE;

ADAPTIVE IMMUNITY; B LYMPHOCYTE; CD4+ T LYMPHOCYTE; CD8+ T LYMPHOCYTE; CELL LINEAGE; CYTOKINE PRODUCTION; DENDRITIC CELL; HUMAN; IMMUNE RESPONSE; IMMUNOREGULATION; IMMUNOTHERAPY; INNATE IMMUNITY; LYMPHOCYTE DIFFERENTIATION; MEMORY CELL; MICROENVIRONMENT; NONHUMAN; REGULATORY MECHANISM; REVIEW;

ANIMALS; CD4-POSITIVE T-LYMPHOCYTES; CELL DIFFERENTIATION; CLONAL ANERGY; HUMANS; IMMUNOLOGIC MEMORY; SIGNAL TRANSDUCTION; VACCINES;

EID: 77957364436     PISSN: 14714914     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.molmed.2010.07.007     Document Type: Review

References (157)

1. Happel K.I., et al. Cutting edge: roles of Toll-like receptor 4 and IL-23 in IL-17 expression in response to Klebsiella pneumoniae infection. J. Immunol. 2003, 170:4432-4436.
2. Bettelli E., et al. Induction and effector functions of T(H)17 cells. Nature 2008, 453:1051-1057.
3. Khader S.A., et al. Th17 cells at the crossroads of innate and adaptive immunity against infectious diseases at the mucosa. Mucosal Immunol. 2009, 2:403-411.
4. Martin-Orozco N., et al. T helper 17 cells promote cytotoxic T cell activation in tumor immunity. Immunity 2009, 31:787-798.
5. Lin Y., et al. Interleukin-17 is required for T helper 1 cell immunity and host resistance to the intracellular pathogen Francisella tularensis. Immunity 2009, 31:799-810.
6. Khader S.A., et al. IL-23 and IL-17 in the establishment of protective pulmonary CD4+ T cell responses after vaccination and during Mycobacterium tuberculosis challenge. Nat. Immunol. 2007, 8:369-377.
7. Hagemann T., et al. Re-educating" tumor-associated macrophages by targeting NF-kappaB. J. Exp. Med. 2008, 205:1261-1268.
8. Belyakov I.M., Ahlers J.D. What role does the route of immunization play in the generation of protective immunity against mucosal pathogens? J. Immunol. 2009, 183:6883-6892.
9. Belyakov I.M., et al. A novel functional CTL avidity/activity compartmentalization to the site of mucosal immunization contributes to protection of macaques against simian/human immunodeficiency viral depletion of mucosal CD4+ T cells. J. Immunol. 2007, 178:7211-7221.
10. Ahlers J.D., Belyakov I.M. Strategies for optimizing targeting and delivery of mucosal HIV vaccines. Eur. J. Immunol. 2009, 39:2657-2669.
11. Belyakov I.M., et al. Mucosal immunization with HIV-1 peptide vaccine induces mucosal and systemic cytotoxic T lymphocytes and protective immunity in mice against intrarectal recombinant HIV-vaccinia challenge. Proc. Natl. Acad. Sci. U. S. A. 1998, 95:1709-1714.
12. Belyakov I.M., et al. Mucosal AIDS vaccine reduces disease and viral load in gut reservoir and blood after mucosal infection of macaques. Nat. Med. 2001, 7:1320-1326.
13. Kwong P.D., Wilson I.A. HIV-1 and influenza antibodies: seeing antigens in new ways. Nat. Immunol. 2009, 10:573-578.
14. Ahlers J.D., Belyakov I.M. Memories that last forever: strategies for optimizing vaccine T-cell memory. Blood 2010, 115:1678-1689.
15. Matzinger P. Friendly and dangerous signals: is the tissue in control? Nat. Immunol. 2007, 8:11-13.
16. Castellino F., Germain R.N. Chemokine-guided CD4+ T cell help enhances generation of IL-6Ralpha high IL-7Ralpha high prememory CD8+ T cells. J. Immunol. 2007, 178:778-787.
17. Bajenoff M., et al. Highways, byways and breadcrumbs: directing lymphocyte traffic in the lymph node. Trends Immunol. 2007, 28:346-352.
18. Dudziak D., et al. Differential antigen processing by dendritic cell subsets in vivo. Science 2007, 315:107-111.
19. Trumpfheller C., et al. The microbial mimic poly IC induces durable and protective CD4+ T cell immunity together with a dendritic cell targeted vaccine. Proc. Natl. Acad. Sci. U. S. A. 2008, 105:2574-2579.
20. Nchinda G., et al. The efficacy of DNA vaccination is enhanced in mice by targeting the encoded protein to dendritic cells. J. Clin. Invest. 2008, 118:1427-1436.
21. Lahoud M.H., et al. The C-type lectin Clec12A present on mouse and human dendritic cells can serve as a target for antigen delivery and enhancement of antibody responses. J. Immunol. 2009, 182:7587-7594.
22. Jongbloed, S.L. et al. (2010) Human CD141+ (BDCA-3)+ dendritic cells (DCs) represent a unique myeloid DC subset that cross-presents necrotic cell antigens. J. Exp. Med. 207, 1247-1260.
23. Ginhoux F., et al. The origin and development of nonlymphoid tissue CD103+ DCs. J. Exp. Med. 2009, 206:3115-3130.
24. Bedoui S., et al. Cross-presentation of viral and self antigens by skin-derived CD103+ dendritic cells. Nat. Immunol. 2009, 10:488-495.
25. Lee H.K., et al. Differential roles of migratory and resident DCs in T cell priming after mucosal or skin HSV-1 infection. J. Exp. Med. 2009, 206:359-370.
26. Izcue A., et al. Regulatory lymphocytes and intestinal inflammation. Annu. Rev. Immunol. 2009, 27:313-338.
27. Bogunovic M., et al. Origin of the lamina propria dendritic cell network. Immunity 2009, 31:513-525.
28. Varol C., et al. Intestinal lamina propria dendritic cell subsets have different origin and functions. Immunity 2009, 31:502-512.
29. Uematsu S., et al. Regulation of humoral and cellular gut immunity by lamina propria dendritic cells expressing Toll-like receptor 5. Nat. Immunol. 2008, 9:769-776.
30. Denning T.L., et al. Lamina propria macrophages and dendritic cells differentially induce regulatory and interleukin 17-producing T cell responses. Nat. Immunol. 2007, 8:1086-1094.
31. Sporri R., Reis e Sousa C. Inflammatory mediators are insufficient for full dendritic cell activation and promote expansion of CD4+ T cell populations lacking helper function. Nat. Immunol. 2005, 6:163-170.
32. Zhu Q., et al. Toll-like receptor ligands synergize through distinct dendritic cell pathways to induce T cell responses: implications for vaccines. Proc. Natl. Acad. Sci. U. S. A. 2008, 105:16260-16265.
33. van Beelen A.J., et al. Stimulation of the intracellular bacterial sensor NOD2 programs dendritic cells to promote interleukin-17 production in human memory T cells. Immunity 2007, 27:660-669.
34. Shaw M.H., et al. T cell-intrinsic role of Nod2 in promoting type 1 immunity to Toxoplasma gondii. Nat. Immunol. 2009, 10:1267-1274.
35. Lavelle E.C., et al. The role of TLRs, NLRs, and RLRs in mucosal innate immunity and homeostasis. Mucosal Immunol. 2010, 3:17-28.
36. Ichinohe T., et al. Inflammasome recognition of influenza virus is essential for adaptive immune responses. J. Exp. Med. 2009, 206:79-87.
37. Dowling D., et al. A comparative analysis of cytokine responses, cell surface marker expression and MAPKs in DCs matured with LPS compared with a panel of TLR ligands. Cytokine 2008, 41:254-262.
38. Jin P., et al. Molecular signatures of maturing dendritic cells: implications for testing the quality of dendritic cell therapies. J. Transl. Med. 2010, 8:4.
39. Gautier G., et al. A type I interferon autocrine-paracrine loop is involved in Toll-like receptor-induced interleukin-12p70 secretion by dendritic cells. J. Exp. Med. 2005, 201:1435-1446.
40. Napolitani G., et al. Selected Toll-like receptor agonist combinations synergistically trigger a T helper type 1-polarizing program in dendritic cells. Nat. Immunol. 2005, 6:769-776.
41. Amsen D., et al. Direct regulation of Gata3 expression determines the T helper differentiation potential of Notch. Immunity 2007, 27:89-99.
42. Warger T., et al. Synergistic activation of dendritic cells by combined Toll-like receptor ligation induces superior CTL responses in vivo. Blood 2006, 108:544-550.
43. Ahlers J.D., Belyakov I.M. Strategies for recruiting and targeting dendritic cells for optimizing HIV vaccines. Trends Mol. Med. 2009, 15:263-274.
44. Ahlers J.D., et al. A push-pull approach to maximize vaccine efficacy: abrogating suppression with an IL-13 inhibitor while augmenting help with GM-CSF and CD40L. Proc. Natl. Acad. Sci. U. S. A. 2002, 99:13020-13025.
45. Heit A., et al. Circumvention of regulatory CD4(+) T cell activity during cross-priming strongly enhances T cell-mediated immunity. Eur. J. Immunol. 2008, 38:1585-1597.
46. Ahlers J.D., et al. Cytokine, chemokine and costimulatory molecule modulation to enhance efficacy of HIV vaccines. Curr. Mol. Med. 2003, 3:285-301.
47. Brooks D.G., et al. IL-10 blockade facilitates DNA vaccine-induced T cell responses and enhances clearance of persistent virus infection. J. Exp. Med. 2008, 205:533-541.
48. Guiducci C., et al. Redirecting in vivo elicited tumor infiltrating macrophages and dendritic cells towards tumor rejection. Cancer Res. 2005, 65:3437-3446.
49. Sui Y., et al. Innate and adaptive immune correlates of vaccine and adjuvant-induced control of mucosal transmission of SIV in macaques. Proc. Natl. Acad. Sci. U. S. A. 2010, 107:9843-9848.
50. Zhu Q., et al. Using 3 TLR ligands as a combination adjuvant induces qualitative changes in T cell responses needed for antiviral protection in mice. J. Clin. Invest. 2010, 120:607-616.
51. Saraiva M., et al. Interleukin-10 production by Th1 cells requires interleukin-12-induced STAT4 transcription factor and ERK MAP kinase activation by high antigen dose. Immunity 2009, 31:209-219.
52. De Luca, A. et al. (2010) IL-22 defines a novel immune pathway of antifungal resistance. Mucosal Immunol. 3, 361-373.
53. O'Connor W., et al. A protective function for interleukin 17A in T cell-mediated intestinal inflammation. Nat. Immunol. 2009, 10:603-609.
54. Muranski P., et al. Tumor-specific Th17-polarized cells eradicate large established melanoma. Blood 2008, 112:362-373.
55. Annunziato F., et al. Phenotypic and functional features of human Th17 cells. J. Exp. Med. 2007, 204:1849-1861.
56. Kader M., et al. Alpha4(+)beta7(hi)CD4(+) memory T cells harbor most Th-17 cells and are preferentially infected during acute SIV infection. Mucosal Immunol. 2009, 2:439-449.
57. Gosselin A., et al. Peripheral blood CCR4+ CCR6+ and CXCR3+ CCR6+ CD4+ T cells are highly permissive to HIV-1 infection. J. Immunol. 2010, 184:1604-1616.
58. Guo L., et al. IL-1 family members and STAT activators induce cytokine production by Th2, Th17, and Th1 cells. Proc. Natl. Acad. Sci. U. S. A. 2009, 106:13463-13468.
59. Imanishi T., et al. Cutting edge: TLR2 directly triggers Th1 effector functions. J. Immunol. 2007, 178:6715-6719.
60. Caron G., et al. Direct stimulation of human T cells via TLR5 and TLR7/8: flagellin and R-848 up-regulate proliferation and IFN-gamma production by memory CD4+ T cells. J. Immunol. 2005, 175:1551-1557.
61. Reynolds J.M., et al. Toll-like receptor 2 signaling in CD4(+) T lymphocytes promotes T helper 17 responses and regulates the pathogenesis of autoimmune disease. Immunity 2010, 32:692-702.
62. Holm C.K., et al. TLR3 ligand polyinosinic:polycytidylic acid induces IL-17A and IL-21 synthesis in human Th cells. J. Immunol. 2009, 183:4422-4431.
63. Annunziato F., et al. The phenotype of human Th17 cells and their precursors, the cytokines that mediate their differentiation and the role of Th17 cells in inflammation. Int. Immunol. 2008, 20:1361-1368.
64. Zhou L., et al. Plasticity of CD4+ T cell lineage differentiation. Immunity 2009, 30:646-655.
65. Schmitt N., et al. Human dendritic cells induce the differentiation of interleukin-21-producing T follicular helper-like cells through interleukin-12. Immunity 2009, 31:158-169.
66. Hsu H.C., et al. Interleukin 17-producing T helper cells and interleukin 17 orchestrate autoreactive germinal center development in autoimmune BXD2 mice. Nat. Immunol. 2008, 9:166-175.
67. Longhi M.P., et al. Dendritic cells require a systemic type I interferon response to mature and induce CD4+ Th1 immunity with poly IC as adjuvant. J. Exp. Med. 2009, 206:1589-1602.
68. Miyagi T., et al. High basal STAT4 balanced by STAT1 induction to control type 1 interferon effects in natural killer cells. J. Exp. Med. 2007, 204:2383-2396.
69. Glimcher L.H., Murphy K.M. Lineage commitment in the immune system: the T helper lymphocyte grows up. Genes Dev. 2000, 14:1693-1711.
70. Szabo S.J., et al. A novel transcription factor, T-bet, directs Th1 lineage commitment. Cell 2000, 100:655-669.
71. Schulz E.G., et al. Sequential polarization and imprinting of type 1 T helper lymphocytes by interferon-gamma and interleukin-12. Immunity 2009, 30:673-683.
72. Kano S., et al. The contribution of transcription factor IRF1 to the interferon-gamma-interleukin 12 signaling axis and TH1 versus TH-17 differentiation of CD4+ T cells. Nat. Immunol. 2008, 9:34-41.
73. Shi M., et al. Janus-kinase-3-dependent signals induce chromatin remodeling at the Ifng locus during T helper 1 cell differentiation. Immunity 2008, 28:763-773.
74. Ivanov I.I., et al. Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell 2009, 139:485-498.
75. Veldhoen M., et al. The aryl hydrocarbon receptor links TH17-cell-mediated autoimmunity to environmental toxins. Nature 2008, 453:106-109.
76. Quintana F.J., et al. Control of T(reg) and T(H)17 cell differentiation by the aryl hydrocarbon receptor. Nature 2008, 453:65-71.
77. Katiyar S.K., et al. Ultraviolet-B exposure of human skin induces cytochromes P450 1A1 and 1B1. J. Invest. Dermatol. 2000, 114:328-333.
78. Zhou L., et al. TGF-beta-induced Foxp3 inhibits T(H)17 cell differentiation by antagonizing RORgammat function. Nature 2008, 453:236-240.
79. Zheng Y., et al. Regulatory T-cell suppressor program co-opts transcription factor IRF4 to control T(H)2 responses. Nature 2009, 458:351-356.
80. Xiao S., et al. Retinoic acid increases Foxp3+ regulatory T cells and inhibits development of Th17 cells by enhancing TGF-beta-driven Smad3 signaling and inhibiting IL-6 and IL-23 receptor expression. J. Immunol. 2008, 181:2277-2284.
81. Maynard C.L., et al. Contrasting roles for all-trans retinoic acid in TGF-beta-mediated induction of Foxp3 and Il10 genes in developing regulatory T cells. J. Exp. Med. 2009, 206:343-357.
82. Pan F., et al. Eos mediates Foxp3-dependent gene silencing in CD4+ regulatory T cells. Science 2009, 325:1142-1146.
83. Bruno L., et al. Runx proteins regulate Foxp3 expression. J. Exp. Med. 2009, 206:2329-2337.
84. Haxhinasto S., et al. The AKT-mTOR axis regulates de novo differentiation of CD4+Foxp3+ cells. J. Exp. Med. 2008, 205:565-574.
85. Hasko G., et al. A(2B) adenosine receptors in immunity and inflammation. Trends Immunol. 2009, 30:263-270.
86. Komatsu N., et al. Heterogeneity of natural Foxp3+ T cells: a committed regulatory T-cell lineage and an uncommitted minor population retaining plasticity. Proc. Natl. Acad. Sci. U. S. A. 2009, 106:1903-1908.
87. Raimondi G., et al. Mammalian target of rapamycin inhibition and alloantigen-specific regulatory T cells synergize to promote long-term graft survival in immunocompetent recipients. J. Immunol. 2010, 184:624-636.
88. Polansky J.K., et al. DNA methylation controls Foxp3 gene expression. Eur. J. Immunol. 2008, 38:1654-1663.
89. June C.H., et al. Engineering lymphocyte subsets: tools, trials and tribulations. Nat. Rev. Immunol. 2009, 9:704-716.
90. Harris T.J., et al. Cutting edge: An in vivo requirement for STAT3 signaling in TH17 development and TH17-dependent autoimmunity. J. Immunol. 2007, 179:4313-4317.
91. Volpe E., et al. A critical function for transforming growth factor-beta, interleukin 23 and proinflammatory cytokines in driving and modulating human T(H)-17 responses. Nat. Immunol. 2008, 9:650-657.
92. Manel N., et al. The differentiation of human T(H)-17 cells requires transforming growth factor-beta and induction of the nuclear receptor RORgammat. Nat. Immunol. 2008, 9:641-649.
93. McGeachy M.J., et al. The interleukin 23 receptor is essential for the terminal differentiation of interleukin 17-producing effector T helper cells in vivo. Nat. Immunol. 2009, 10:314-324.
94. LeibundGut-Landmann S., et al. Syk- and CARD9-dependent coupling of innate immunity to the induction of T helper cells that produce interleukin 17. Nat. Immunol. 2007, 8:630-638.
95. Acosta-Rodriguez E.V., et al. Surface phenotype and antigenic specificity of human interleukin 17-producing T helper memory cells. Nat. Immunol. 2007, 8:639-646.
96. Ouyang W., et al. The biological functions of T helper 17 cell effector cytokines in inflammation. Immunity 2008, 28:454-467.
97. Volpe E., et al. Multiparametric analysis of cytokine-driven human Th17 differentiation reveals a differential regulation of IL-17 and IL-22 production. Blood 2009, 114:3610-3614.
98. Romagnani S., et al. Properties and origin of human Th17 cells. Mol. Immunol. 2009, 47:3-7.
99. Awasthi A., et al. A dominant function for interleukin 27 in generating interleukin 10-producing anti-inflammatory T cells. Nat. Immunol. 2007, 8:1380-1389.
100. O'Garra A., Vieira P. T(H)1 cells control themselves by producing interleukin-10. Nat. Rev. Immunol. 2007, 7:425-428.
101. Pot C., et al. Cutting edge: IL-27 induces the transcription factor c-Maf, cytokine IL-21, and the costimulatory receptor ICOS that coordinately act together to promote differentiation of IL-10-producing Tr1 cells. J. Immunol. 2009, 183:797-801.
102. Lee Y.K., et al. Late developmental plasticity in the T helper 17 lineage. Immunity 2009, 30:92-107.
103. Diveu C., et al. IL-27 blocks RORc expression to inhibit lineage commitment of Th17 cells. J. Immunol. 2009, 182:5748-5756.
104. Anderson C.F., et al. IL-27 regulates IL-10 and IL-17 from CD4+ cells in nonhealing Leishmania major infection. J. Immunol. 2009, 183:4619-4627.
105. Zhang X., et al. IFN-beta1a inhibits the secretion of Th-17-polarizing cytokines in human dendritic cells via TLR7 up-regulation. J. Immunol. 2009, 182:3928-3936.
106. Cejas P.J., et al. TRAF6 inhibits Th17 differentiation and TGF-{beta}-mediated suppression of IL-2. Blood 2010, 115:4750-4757.
107. Pellegrini M., et al. Adjuvant IL-7 antagonizes multiple cellular and molecular inhibitory networks to enhance immunotherapies. Nat. Med. 2009, 15:528-536.
108. Novy P., et al. CD4 T cells are required for CD8 T cell survival during both primary and memory recall responses. J. Immunol. 2007, 179:8243-8251.
109. Janssen E.M., et al. CD4+ T cells are required for secondary expansion and memory in CD8+ T lymphocytes. Nature 2003, 421:852-856.
110. Hernandez M.G., et al. CD40 on APCs is needed for optimal programming, maintenance, and recall of CD8+ T cell memory even in the absence of CD4+ T cell help. J. Immunol. 2008, 180:4382-4390.
111. Hernandez M.G., et al. CD40-CD40 ligand interaction between dendritic cells and CD8+ T cells is needed to stimulate maximal T cell responses in the absence of CD4+ T cell help. J. Immunol. 2007, 178:2844-2852.
112. Johnson S., et al. Selected Toll-like receptor ligands and viruses promote helper-independent cytotoxic T cell priming by upregulating CD40L on dendritic cells. Immunity 2009, 30:218-227.
113. Stone G.W., et al. Nanoparticle-delivered multimeric soluble CD40L DNA combined with Toll-like receptor agonists as a treatment for melanoma. PLoS One 2009, 4:e7334.
114. Nakanishi Y., et al. CD8(+) T lymphocyte mobilization to virus-infected tissue requires CD4(+) T-cell help. Nature 2009, 462:510-513.
115. Keller A.M., et al. Costimulatory ligand CD70 is delivered to the immunological synapse by shared intracellular trafficking with MHC class II molecules. Proc. Natl. Acad. Sci. U. S. A. 2007, 104:5989-5994.
116. van Oosterwijk M.F., et al. CD27-CD70 interactions sensitise naive CD4+ T cells for IL-12-induced Th1 cell development. Int. Immunol. 2007, 19:713-718.
117. Xiao Y., et al. CD27 instructs CD4+ T cells to provide help for the memory CD8+ T cell response after protein immunization. J. Immunol. 2008, 181:1071-1082.
118. French R.R., et al. Eradication of lymphoma by CD8 T cells following anti-CD40 monoclonal antibody therapy is critically dependent on CD27 costimulation. Blood 2007, 109:4810-4815.
119. Laouar A., et al. CD70+ antigen-presenting cells control the proliferation and differentiation of T cells in the intestinal mucosa. Nat. Immunol. 2005, 6:698-706.
120. Turtle C.J., et al. A distinct subset of self-renewing human memory CD8+ T cells survives cytotoxic chemotherapy. Immunity 2009, 31:834-844.
121. Gattinoni L., et al. Wnt signaling arrests effector T cell differentiation and generates CD8+ memory stem cells. Nat. Med. 2009, 15:808-813.
122. Surh C.D., Sprent J. Homeostasis of naive and memory T cells. Immunity 2008, 29:848-862.
123. Northrop J.K., et al. Epigenetic remodeling of the IL-2 and IFN-gamma loci in memory CD8 T cells is influenced by CD4 T cells. J. Immunol. 2006, 177:1062-1069.
124. Northrop J.K., et al. Cutting edge: chromatin remodeling as a molecular basis for the enhanced functionality of memory CD8 T cells. J. Immunol. 2008, 181:865-868.
125. Pearce E.L., et al. Enhancing CD8 T-cell memory by modulating fatty acid metabolism. Nature 2009, 460:103-107.
126. Gupta M., et al. Inhibition of histone deacetylase overcomes rapamycin-mediated resistance in diffuse large B-cell lymphoma by inhibiting Akt signaling through mTORC2. Blood 2009, 114:2926-2935.
127. Hendrickson A.W., et al. Anticancer therapy: boosting the bang of Bim. J. Clin. Invest. 2008, 118:3582-3584.
128. King C.G., et al. Cutting edge: requirement for TRAF6 in the induction of T cell anergy. J. Immunol. 2008, 180:34-38.
129. Zhang J., et al. The type III histone deacetylase Sirt1 is essential for maintenance of T cell tolerance in mice. J. Clin. Invest. 2009, 119:3048-3058.
130. Fritsch R.D., et al. Stepwise differentiation of CD4 memory T cells defined by expression of CCR7 and CD27. J. Immunol. 2005, 175:6489-6497.
131. Lohning M., et al. Long-lived virus-reactive memory T cells generated from purified cytokine-secreting T helper type 1 and type 2 effectors. J. Exp. Med. 2008, 205:53-61.
132. Harrington L.E., et al. Memory CD4 T cells emerge from effector T-cell progenitors. Nature 2008, 452:356-360.
133. Adeeku E., et al. Flexibility accompanies commitment of memory CD4 lymphocytes derived from IL-4 locus-activated precursors. Proc. Natl. Acad. Sci. U. S. A. 2008, 105:9307-9312.
134. Guimond M., et al. Interleukin 7 signaling in dendritic cells regulates the homeostatic proliferation and niche size of CD4+ T cells. Nat. Immunol. 2009, 10:149-157.
135. Tokoyoda K., et al. Professional memory CD4+ T lymphocytes preferentially reside and rest in the bone marrow. Immunity 2009, 30:721-730.
136. Wells A.D. New insights into the molecular basis of T cell anergy: anergy factors, avoidance sensors, and epigenetic imprinting. J. Immunol. 2009, 182:7331-7341.
137. Longhi M.P., et al. Interleukin-6 is crucial for recall of influenza-specific memory CD4 T cells. PLoS Pathog. 2008, 4:e1000006.
138. Li Q.J., et al. miR-181a is an intrinsic modulator of T cell sensitivity and selection. Cell 2007, 129:147-161.
139. Wei G., et al. Global mapping of H3K4me3 and H3K27me3 reveals specificity and plasticity in lineage fate determination of differentiating CD4+ T cells. Immunity 2009, 30:155-167.
140. Reese T.A., et al. Chitin induces accumulation in tissue of innate immune cells associated with allergy. Nature 2007, 447:92-96.
141. Ito T., et al. TSLP-activated dendritic cells induce an inflammatory T helper type 2 cell response through OX40 ligand. J. Exp. Med. 2005, 202:1213-1223.
142. Yang D., et al. Eosinophil-derived neurotoxin acts as an alarmin to activate the TLR2-MyD88 signal pathway in dendritic cells and enhances Th2 immune responses. J. Exp. Med. 2008, 205:79-90.
143. Eagar T.N., et al. Notch 1 signaling regulates peripheral T cell activation. Immunity 2004, 20:407-415.
144. Wiethe C., et al. Dendritic cell differentiation state and their interaction with NKT cells determine Th1/Th2 differentiation in the murine model of Leishmania major infection. J. Immunol. 2008, 180:4371-4381.
145. Krishnamoorthy N., et al. Activation of c-Kit in dendritic cells regulates T helper cell differentiation and allergic asthma. Nat. Med. 2008, 14:565-573.
146. Jenner R.G., et al. The transcription factors T-bet and GATA-3 control alternative pathways of T-cell differentiation through a shared set of target genes. Proc. Natl. Acad. Sci. U. S. A. 2009, 106:17876-17881.
147. Zhou X., et al. Instability of the transcription factor Foxp3 leads to the generation of pathogenic memory T cells in vivo. Nat. Immunol. 2009, 10:1000-1007.
148. Du C., et al. MicroRNA miR-326 regulates TH-17 differentiation and is associated with the pathogenesis of multiple sclerosis. Nat. Immunol. 2009, 10:1252-1259.
149. Brucklacher-Waldert V., et al. Phenotypical characterization of human Th17 cells unambiguously identified by surface IL-17A expression. J. Immunol. 2009, 183:5494-5501.
150. Shevach E.M. Mechanisms of foxp3+ T regulatory cell-mediated suppression. Immunity 2009, 30:636-645.
151. Wang L., et al. Programmed death 1 ligand signaling regulates the generation of adaptive Foxp3+CD4+ regulatory T cells. Proc. Natl. Acad. Sci. U. S. A. 2008, 105:9331-9336.
152. Howie D., et al. MS4A4B is a GITR-associated membrane adapter, expressed by regulatory T cells, which modulates T cell activation. J. Immunol. 2009, 183:4197-4204.
153. Strauss L., et al. Human circulating CD4+CD25highFoxp3+ regulatory T cells kill autologous CD8+ but not CD4+ responder cells by Fas-mediated apoptosis. J. Immunol. 2009, 182:1469-1480.
154. Kubach J., et al. Human CD4+CD25+ regulatory T cells: proteome analysis identifies galectin-10 as a novel marker essential for their anergy and suppressive function. Blood 2007, 110:1550-1558.
155. Becker C., et al. Protection from graft-versus-host disease by HIV-1 envelope protein gp120-mediated activation of human CD4+CD25+ regulatory T cells. Blood 2009, 114:1263-1269.
156. Curti A., et al. The role of indoleamine 2,3-dioxygenase in the induction of immune tolerance: focus on hematology. Blood 2009, 113:2394-2401.
157. Manches O., et al. HIV-activated human plasmacytoid DCs induce Tregs through an indoleamine 2,3-dioxygenase-dependent mechanism. J. Clin. Invest. 2008, 118:3431-3439.