Naive tumor-specific CD4+ T cells differentiated in vivo eradicate established melanoma

Journal of Experimental Medicine

Volumn 207, Issue 3, 2010, Pages 651-667

  Xie, Ying ^a   Akpinarli, Akgül ^c   Maris, Charles ^d   Hipkiss, Edward L ^d   Lane, Malcolm ^a   Kwon, Eun Kyung M ^a   Muranski, Pawel ^e   Restifo, Nicholas P ^e   Antony, Paul Andrew ^a,b  

^a UNIVERSITY OF MARYLAND SCHOOL OF MEDICINE   (United States)

^b UNIVERSITY OF MARYLAND   (United States)

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

^d JOHNS HOPKINS UNIVERSITY SCHOOL OF MEDICINE   (United States)

^e NATIONAL CANCER INSTITUTE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CHEMOKINE; CYTOKINE; GAMMA INTERFERON ANTIBODY; MAJOR HISTOCOMPATIBILITY ANTIGEN CLASS 2; TYROSINASE RELATED PROTEIN 1;

ADOPTIVE TRANSFER; ANTIGEN RECOGNITION; ANTINEOPLASTIC ACTIVITY; ARTICLE; AUTOIMMUNITY; CANCER IMMUNIZATION; CANCER IMMUNOTHERAPY; CANCER RISK; CD4+ T LYMPHOCYTE; CD8+ T LYMPHOCYTE; CELL SURVIVAL; CYTOKINE PRODUCTION; CYTOTOXIC T LYMPHOCYTE; FLOW CYTOMETRY; HELPER CELL; HUMAN; IMMUNE DEFICIENCY; LYMPHOCYTE ACTIVATION; LYMPHOCYTE DIFFERENTIATION; LYMPHOCYTOPENIA; MELANOMA; NATURAL KILLER T CELL; NONHUMAN; PRIORITY JOURNAL; SCANNING ELECTRON MICROSCOPY; SIGNAL TRANSDUCTION;

ADOPTIVE TRANSFER; ANIMALS; ANTIGENS, CD4; CD4-POSITIVE T-LYMPHOCYTES; CD8-POSITIVE T-LYMPHOCYTES; CELL DIFFERENTIATION; HUMANS; IMMUNOTHERAPY, ADOPTIVE; INTERFERON TYPE I; MELANOMA; MELANOMA, EXPERIMENTAL; MICE; PREGNANCY PROTEINS;

EID: 77949530108     PISSN: 00221007     EISSN: 15409538     Source Type: Journal    
DOI: 10.1084/jem.20091921     Document Type: Article

References (86)

1. Antony, P.A., C.A. Piccirillo, A. Akpinarli, S.E. Finkelstein, P.J. Speiss, D.R. Surman, D.C. Palmer, C.C. Chan, C.A. Klebanoff, W.W. Overwijk, et al. 2005. CD8+ T cell immunity against a tumor/self-antigen is augmented by CD4+ T helper cells and hindered by naturally occurring T regulatory cells. J. Immunol. 174:2591-2601.
2. Antony, P.A., C.M. Paulos, M. Ahmadzadeh, A. Akpinarli, D.C. Palmer, N. Sato, A. Kaiser, C.S. Hinrichs, C. Heinrichs, C.A. Klebanoff, et al. 2006. Interleukin-2-dependent mechanisms of tolerance and immunity in vivo. J. Immunol. 176:5255-5266.
3. Banchereau, J., E. Klechevsky, N. Schmitt, R. Morita, K. Palucka, and H. Ueno. 2009. Harnessing human dendritic cell subsets to design novel vaccines. Ann. N. Y. Acad. Sci. 1174:24-32. doi:10.1111/j.1749-6632.2009.04999.x
4. Behrens, G., M. Li, C.M. Smith, G.T. Belz, J. Mintern, F.R. Carbone, and W.R. Heath. 2004a. Helper T cells, dendritic cells and CTL Immunity. Immunol. Cell Biol. 82:84-90. doi:10.1111/j.1440-1711.2004.01211.x
5. Behrens, G.M., M. Li, G.M. Davey, J. Allison, R.A. Flavell, F.R. Carbone, and W.R. Heath. 2004b. Helper requirements for generation of effector CTL to islet beta cell antigens. J. Immunol. 172:5420-5426.
6. Belfiore, A., T. Mauerhoff, R. Pujol-Borrell, K. Badenhoop, M. Buscema, R. Mirakian, and G.F. Bottazzo. 1991. De novo HLA class II and enhanced HLA class I molecule expression in SV40 transfected human thyroid epithelial cells. J. Autoimmun. 4:397-414. doi:10.1016/0896-8411 (91)901556
7. Bennett, S.R., F.R. Carbone, F. Karamalis, R.A. Flavell, J.F. Miller, and W.R. Heath. 1998. Help for cytotoxic-T-cell responses is mediated by CD40 signalling. Nature. 393:478-480. doi:10.1038/30996
8. Beutner, U., and H.R. MacDonald. 1998. TCR-MHC class II interaction is required for peripheral expansion of CD4 cells in a T cell-deficient host. Int. Immunol. 10:305-310. doi:10.1093/intimm/10.3.305
9. Boyman, O., M. Kovar, M.P. Rubinstein, C.D. Surh, and J. Sprent. 2006. Selective stimulation of T cell subsets with antibody-cytokine immune complexes. Science. 311:1924-1927. doi:10.1126/science.1122927
10. Boyman, O., C. Ramsey, D.M. Kim, J. Sprent, and C.D. Surh. 2008. IL-7/anti-IL-7 mAb complexes restore T cell development and induce homeostatic T cell expansion without lymphopenia. J. Immunol. 180:7265-7275.
11. Brandmaier, A.G., W.W. Leitner, S.P. Ha, J. Sidney, N.P. Restifo, and C.E. Touloukian. 2009. High-avidity autoreactive CD4+ T cells induce host CTL, overcome T(regs) and mediate tumor destruction. J. Immunother. 32:677-688. doi:10.1097/CJI.0b013e3181ab1824
12. Cao, X., E.W. Shores, J. Hu-Li, M.R. Anver, B.L. Kelsall, S.M. Russell, J. Drago, M. Noguchi, A. Grinberg, E.T. Bloom, et al. 1995. Defective lymphoid development in mice lacking expression of the common cytokine receptor gamma chain. Immunity. 2:223-238. doi:10.1016/1074-7613(95)90047-0
13. Cho, J.H., O. Boyman, H.O. Kim, B. Hahm, M.P. Rubinstein, C. Ramsey, D.M. Kim, C.D. Surh, and J. Sprent. 2007. An intense form of homeostatic proliferation of naive CD8+ cells driven by IL-2. J. Exp. Med. 204:1787-1801. doi:10.1084/jem.20070740
14. Corthay, A., D.K. Skovseth, K.U. Lundin, E. Røsjø, H. Omholt, P.O. Hofgaard, G. Haraldsen, and B. Bogen. 2005. Primary antitumor immune response mediated by CD4+ T cells. Immunity. 22:371-383. doi:10.1016/j.immuni.2005.02.003
15. Diehl, L., A.T. den Boer, S.P. Schoenberger, E.I. van der Voort, T.N. Schumacher, C.J. Melief, R. Offringa, and R.E. Toes. 1999. CD40 activation in vivo overcomes peptide-induced peripheral cytotoxic T-lymphocyte tolerance and augments anti-tumor vaccine efficacy. Nat. Med. 5:774-779. doi:10.1038/10495
16. Dougan, M., and G. Dranoff. 2009. Immune therapy for cancer. Annu. Rev. Immunol. 27:83-117. doi:10.1146/annurev.immunol.021908.132544
17. Dubsky, P., H. Saito, M. Leogier, C. Dantin, J.E. Connolly, J. Banchereau, and A.K. Palucka. 2007. IL-15-induced human DC efficiently prime melanoma-specific naive CD8+ T cells to differentiate into CTL. Eur. J. Immunol. 37:1678-1690. doi:10.1002/eji.200636329
18. Dudley, M.E., J.R. Wunderlich, P.F. Robbins, J.C. Yang, P. Hwu, D.J. Schwartzentruber, S.L. Topalian, R. Sherry, N.P. Restifo, A.M. Hubicki, et al. 2002. Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science. 298:850-854. doi:10.1126/science. 1076514
19. Dudley, M.E., J.R. Wunderlich, J.C. Yang, R.M. Sherry, S.L. Topalian, N.P. Restifo, R.E. Royal, U. Kammula, D.E. White, S.A. Mavroukakis, et al. 2005. Adoptive cell transfer therapy following non-myeloablative but lymphodepleting chemotherapy for the treatment of patients with refractory metastatic melanoma. J. Clin. Oncol. 23:2346-2357. doi: 10.1200/JCO.2005.00.240
20. Dudley, M.E., J.C. Yang, R. Sherry, M.S. Hughes, R. Royal, U. Kammula, P.F. Robbins, J. Huang, D.E. Citrin, S.F. Leitman, et al. 2008. Adoptive cell therapy for patients with metastatic melanoma: evaluation of intensive myeloablative chemoradiation preparative regimens. J. Clin. Oncol. 26:5233-5239. doi:10.1200/JCO.2008.16.5449
21. Engelhorn, M.E., J.A. Guevara-Patiño, G. Noffz, A.T. Hooper, O. Lou, J.S. Gold, B.J. Kappel, and A.N. Houghton. 2006. Autoimmunity and tumor immunity induced by immune responses to mutations in self. Nat. Med. 12:198-206. doi:10.1038/nm1363
22. Gattinoni, L., S.E. Finkelstein, C.A. Klebanoff, P.A. Antony, D.C. Palmer, P.J. Spiess, L.N. Hwang, Z. Yu, C. Wrzesinski, D.M. Heimann, et al. 2005a. Removal of homeostatic cytokine sinks by lymphodepletion enhances the efficacy of adoptively transferred tumor-specific CD8+ T cells. J. Exp. Med. 202:907-912. doi:10.1084/jem.20050732
23. Gattinoni, L., C.A. Klebanoff, D.C. Palmer, C. Wrzesinski, K. Kerstann, Z. Yu, S.E. Finkelstein, M.R. Theoret, S.A. Rosenberg, and N.P. Restifo. 2005b. Acquisition of full effector function in vitro paradoxically impairs the in vivo antitumor efficacy of adoptively transferred CD8+ T cells. J. Clin. Invest. 115:1616-1626. doi:10.1172/JCI24480
24. Gattinoni, L., D.J. Powell Jr., S.A. Rosenberg, and N.P. Restifo. 2006. Adoptive immunotherapy for cancer: building on success. Nat. Rev. Immunol. 6:383-393. doi:10.1038/nri1842
25. Gattinoni, L., X.S. Zhong, D.C. Palmer, Y. Ji, C.S. Hinrichs, Z. Yu, C. Wrzesinski, A. Boni, L. Cassard, L.M. Garvin, et al. 2009. Wnt signaling arrests effector T cell differentiation and generates CD8+ memory stem cells. Nat. Med. 15:808-813. doi:10.1038/nm.1982
26. Guimond, M., R.G. Veenstra, D.J. Grindler, H. Zhang, Y. Cui, R.D. Murphy, S.Y. Kim, R. Na, L. Hennighausen, S. Kurtulus, et al. 2009. Interleukin 7 signaling in dendritic cells regulates the homeostatic proliferation and niche size of CD4+ T cells. Nat. Immunol. 10:149-157. doi:10.1038/ni.1695
27. Hinrichs, C.S., Z.A. Borman, L. Cassard, L. Gattinoni, R. Spolski, Z. Yu, L. Sanchez-Perez, P. Muranski, S.J. Kern, C. Logun, et al. 2009. Adoptively transferred effector cells derived from naive rather than central memory CD8+ T cells mediate superior antitumor immunity. Proc. Natl. Acad. Sci. USA. 106:17469-17474. doi:10.1073/pnas.0907448106
28. Ho, W.Y., C. Yee, and P.D. Greenberg. 2002. Adoptive therapy with CD8(+) T cells: it may get by with a little help from its friends. J. Clin. Invest. 110:1415-1417.
29. Hunder, N.N., H. Wallen, J. Cao, D.W. Hendricks, J.Z. Reilly, R. Rodmyre, A. Jungbluth, S. Gnjatic, J.A. Thompson, and C. Yee. 2008. Treatment of metastatic melanoma with autologous CD4+ T cells against NY-ESO-1. N. Engl. J. Med. 358:2698-2703. doi:10.1056/NEJMoa0800251
30. Hung, K., R. Hayashi, A. Lafond-Walker, C. Lowenstein, D. Pardoll, and H. Levitsky. 1998. The central role of CD4+ T cells in the antitumor immune response. J. Exp. Med. 188:2357-2368. doi:10.1084/jem.188.12.2357
31. Janssen, E.M., E.E. Lemmens, T. Wolfe, U. Christen, M.G. von Herrath, and S.P. Schoenberger. 2003. CD4+ T cells are required for secondary expansion and memory in CD8+ T lymphocytes. Nature. 421:852-856. doi:10.1038/ nature01441
32. Johnson, L.A., R.A. Morgan, M.E. Dudley, L. Cassard, J.C. Yang, M.S. Hughes, U.S. Kammula, R.E. Royal, R.M. Sherry, J.R. Wunderlich, et al. 2009. Gene therapy with human and mouse T-cell receptors mediates cancer regression and targets normal tissues expressing cognate antigen. Blood. 114:535-546. doi:10.1182/blood-2009-03-211714
33. Kahn, M., H. Sugawara, P. McGowan, K. Okuno, S. Nagoya, K.E. Hellström, I. Hellström, and P. Greenberg. 1991. CD4+ T cell clones specific for the human p97 melanoma-associated antigen can eradicate pulmonary metastases from a murine tumor expressing the p97 antigen. J. Immunol. 146:3235-3241.
34. Kalams, S.A., and B.D. Walker. 1998. The critical need for CD4 help in maintaining effective cytotoxic T lymphocyte responses. J. Exp. Med. 188:2199-2204. doi:10.1084/jem.188.12.2199
35. Kassiotis, G., R. Zamoyska, and B. Stockinger. 2003. Involvement of avidity for major histocompatibility complex in homeostasis of naive and memory T cells. J. Exp. Med. 197:1007-1016. doi:10.1084/jem.20021812
36. Kim, J.M., J.P. Rasmussen, and A.Y. Rudensky. 2007. Regulatory T cells prevent catastrophic autoimmunity throughout the lifespan of mice. Nat. Immunol. 8:191-197. doi:10.1038/ni1428
37. Klebanoff, C.A., L. Gattinoni, P. Torabi-Parizi, K. Kerstann, A.R. Cardones, S.E. Finkelstein, D.C. Palmer, P.A. Antony, S.T. Hwang, S.A. Rosenberg, et al. 2005. Central memory self/tumor-reactive CD8+ T cells confer superior antitumor immunity compared with effector memory T cells. Proc. Natl. Acad. Sci. USA. 102:9571-9576. doi:10.1073/pnas.0503726102
38. Klebanoff, C.A., Z. Yu, L.N. Hwang, D.C. Palmer, L. Gattinoni, and N.P. Restifo. 2009. Programming tumor-reactive effector memory CD8+ T cells in vitro obviates the requirement for in vivo vaccination. Blood. 114:1776-1783. doi:10.1182/blood-2008-12-192419
39. Luster, A.D., J.C. Unkeless, and J.V. Ravetch. 1985. Gamma-interferon transcriptionally regulates an early-response gene containing homology to platelet proteins. Nature. 315:672-676. doi:10.1038/315672a0
40. Martín-Fontecha, A., L.L. Thomsen, S. Brett, C. Gerard, M. Lipp, A. Lanzavecchia, and F. Sallusto. 2004. Induced recruitment of NK cells to lymph nodes provides IFN-gamma for T(H)1 priming. Nat. Immunol. 5:1260-1265. doi:10.1038/ni1138
41. Marzo, A.L., B.F. Kinnear, R.A. Lake, J.J. Frelinger, E.J. Collins, B.W. Robinson, and B. Scott. 2000. Tumor-specific CD4+ T cells have a major "post-licensing" role in CTL mediated anti-tumor immunity. J. Immunol. 165:6047-6055.
42. McNamara, J.O., D. Kolonias, F. Pastor, R.S. Mittler, L. Chen, P.H. Giangrande, B. Sullenger, and E. Gilboa. 2008. Multivalent 4-1BB binding aptamers costimulate CD8+ T cells and inhibit tumor growth in mice. J. Clin. Invest. 118:376-386. doi:10.1172/JCI33365
43. Menke, J., G.C. Zeller, E. Kikawada, T.K. Means, X.R. Huang, H.Y. Lan, B. Lu, J. Farber, A.D. Luster, and V.R. Kelley. 2008. CXCL9, but not CXCL10, promotes CXCR3-dependent immune-mediated kidney disease. J. Am. Soc. Nephrol. 19:1177-1189. doi:10.1681/ASN.2007111179
44. Morgan, R.A., M.E. Dudley, J.R. Wunderlich, M.S. Hughes, J.C. Yang, R.M. Sherry, R.E. Royal, S.L. Topalian, U.S. Kammula, N.P. Restifo, et al. 2006. Cancer regression in patients after transfer of genetically engineered lymphocytes. Science. 314:126-129. doi:10.1126/science.1129003
45. Mumberg, D., P.A. Monach, S. Wanderling, M. Philip, A.Y. Toledano, R.D. Schreiber, and H. Schreiber. 1999. CD4(+) T cells eliminate MHC class II-negative cancer cells in vivo by indirect effects of IFN-gamma. Proc. Natl. Acad. Sci. USA. 96:8633-8638. doi:10.1073/pnas.96.15.8633
46. Muranski, P., and N.P. Restifo. 2009. Adoptive immunotherapy of cancer using CD4(+) T cells. Curr. Opin. Immunol. 21:200-208. doi:10.1016/j.coi.2009.02.004
47. Muranski, P., A. Boni, P.A. Antony, L. Cassard, K.R. Irvine, A. Kaiser, C.M. Paulos, D.C. Palmer, C.E. Touloukian, K. Ptak, et al. 2008. Tumor-specific Th17-polarized cells eradicate large established melanoma. Blood. 112:362-373. doi:10.1182/blood-2007-11-120998
48. Nakano, H., K.L. Lin, M. Yanagita, C. Charbonneau, D.N. Cook, T. Kakiuchi, and M.D. Gunn. 2009. Blood-derived inflammatory dendritic cells in lymph nodes stimulate acute T helper type 1 immune responses. Nat. Immunol. 10:394-402. doi:10.1038/ni.1707
49. Nishimura, T., K. Iwakabe, M. Sekimoto, Y. Ohmi, T. Yahata, M. Nakui, T. Sato, S. Habu, H. Tashiro, M. Sato, and A. Ohta. 1999. Distinct role of antigen-specific T helper type 1 (Th1) and Th2 cells in tumor eradication in vivo. J. Exp. Med. 190:617-627. doi:10.1084/jem.190.5.617
50. Ohteki, T., K. Suzue, C. Maki, T. Ota, and S. Koyasu. 2001. Critical role of IL-15-IL-15R for antigen-presenting cell functions in the innate immune response. Nat. Immunol. 2:1138-1143. doi:10.1038/ni729
51. Ohteki, T., H. Tada, K. Ishida, T. Sato, C. Maki, T. Yamada, J. Hamuro, and S. Koyasu. 2006. Essential roles of DC-derived IL-15 as a mediator of inflammatory responses in vivo. J. Exp. Med. 203:2329-2338. doi:10.1084/jem.20061297
52. + T cells. J. Exp. Med. 198:569-580. doi:10.1084/jem.20030590
53. Palmer, D.C., C.C. Chan, L. Gattinoni, C. Wrzesinski, C.M. Paulos, C.S. Hinrichs, D.J. Powell Jr., C.A. Klebanoff, S.E. Finkelstein, R.N. Fariss, et al. 2008. Effective tumor treatment targeting a melanoma/melanocyte-associated antigen triggers severe ocular autoimmunity. Proc. Natl. Acad. Sci. USA. 105:8061-8066. doi:10.1073/pnas.0710929105
54. Palucka, A.K., H. Ueno, J.W. Fay, and J. Banchereau. 2007. Taming cancer by inducing immunity via dendritic cells. Immunol. Rev. 220:129-150. doi:10.1111/j.1600-065X.2007.00575.x
55. Paulos, C.M., C. Wrzesinski, A. Kaiser, C.S. Hinrichs, M. Chieppa, L. Cassard, D.C. Palmer, A. Boni, P. Muranski, Z. Yu, et al. 2007. Microbial translocation augments the function of adoptively transferred self/tumor-specific CD8+ T cells via TLR4 signaling. J. Clin. Invest. 117:2197-2204. doi:10.1172/JCI32205
56. Peggs, K.S., S.A. Quezada, C.A. Chambers, A.J. Korman, and J.P. Allison. 2009. Blockade of CTLA-4 on both effector and regulatory T cell compartments contributes to the antitumor activity of anti-CTLA-4 antibodies. J. Exp. Med. 206:1717-1725. doi:10.1084/jem.20082492
57. Pellegrini, M., T. Calzascia, A.R. Elford, A. Shahinian, A.E. Lin, D. Dissanayake, S. Dhanji, L.T. Nguyen, M.A. Gronski, M. Morre, et al. 2009. Adjuvant IL-7 antagonizes multiple cellular and molecular inhibitory networks to enhance immunotherapies. Nat. Med. 15:528-536. doi:10.1038/nm.1953
58. Perez-Diez, A., N.T. Joncker, K. Choi, W.F. Chan, C.C. Anderson, O. Lantz, and P. Matzinger. 2007. CD4 cells can be more efficient at tumor rejection than CD8 cells. Blood. 109:5346-5354. doi:10.1182/blood-2006- 10-051318
59. Pule, M.A., B. Savoldo, G.D. Myers, C. Rossig, H.V. Russell, G. Dotti, M.H. Huls, E. Liu, A.P. Gee, Z. Mei, et al. 2008. Virus-specific T cells engineered to coexpress tumor-specific receptors: persistence and anti-tumor activity in individuals with neuroblastoma. Nat. Med. 14:1264-1270. doi:10.1038/nm.1882
60. Qin, Z., and T. Blankenstein. 2000. CD4+ T cell-mediated tumor rejection involves inhibition of angiogenesis that is dependent on IFN gamma receptor expression by nonhematopoietic cells. Immunity. 12:677-686. doi:10.1016/S1074-7613(00)80218-6
61. Quezada, S.A., K.S. Peggs, M.A. Curran, and J.P. Allison. 2006. CTLA4 blockade and GM-CSF combination immunotherapy alters the intratumor balance of effector and regulatory T cells. J. Clin. Invest. 116: 1935-1945. doi:10.1172/JCI27745
62. Quezada, S.A., K.S. Peggs, T.R. Simpson, Y. Shen, D.R. Littman, and J.P. Allison. 2008. Limited tumor infiltration by activated T effector cells restricts the therapeutic activity of regulatory T cell depletion against established melanoma. J. Exp. Med. 205:2125-2138. doi:10.1084/jem. 20080099
63. Quezada, S.A., T.R. Simpson, K.S. Peggs, T. Merghoub, J. Vider, X. Fan, R. Blasberg, H. Yagita, P. Muranski, P.A. Antony, N.P. Restifo, and J.P. Allison. 2010. Tumor-reactive CD4+ T cells develop cytotoxic activity and eradicate large established melanoma after transfer into lymphopenic hosts. J. Exp. Med. 207:637-650. doi:10.1084/jem.20091918
64. Raulet, D.H., and N. Guerra. 2009. Oncogenic stress sensed by the immune system: role of natural killer cell receptors. Nat. Rev. Immunol. 9:568-580. doi:10.1038/nri2604
65. Ridge, J.P., F. Di Rosa, and P. Matzinger. 1998. A conditioned dendritic cell can be a temporal bridge between a CD4+ T-helper and a T-killer cell. Nature. 393:474-478. doi:10.1038/30989
66. Robinson, D.S., and A. O'Garra. 2002. Further checkpoints in Th1 development. Immunity. 16:755-758. doi:10.1016/S1074-7613(02)00331-X
67. Rosenberg, S.A. 2001. Progress in human tumour immunology and immunotherapy. Nature. 411:380-384. doi:10.1038/35077246
68. Rosenberg, S.A., N.P. Restifo, J.C. Yang, R.A. Morgan, and M.E. Dudley. 2008. Adoptive cell transfer: a clinical path to effective cancer immunotherapy. Nat. Rev. Cancer. 8:299-308. doi:10.1038/nrc2355
69. Rubinstein, M.P., M. Kovar, J.F. Purton, J.H. Cho, O. Boyman, C.D. Surh, and J. Sprent. 2006. Converting IL-15 to a superagonist by binding to soluble IL-15Ralpha. Proc. Natl. Acad. Sci. USA. 103:9166-9171. doi:10.1073/pnas.0600240103
70. Smyth, I.M., L. Wilming, A.W. Lee, M.S. Taylor, P. Gautier, K. Barlow, J. Wallis, S. Martin, R. Glithero, B. Phillimore, et al. 2006. Genomic anatomy of the Tyrp1 (brown) deletion complex. Proc. Natl. Acad. Sci. USA. 103:3704-3709. doi:10.1073/pnas.0600199103
71. Sotomayor, E.M., I. Borrello, E. Tubb, F.M. Rattis, H. Bien, Z. Lu, S. Fein, S. Schoenberger, and H.I. Levitsky. 1999. Conversion of tumorspecific CD4+ T-cell tolerance to T-cell priming through in vivo ligation of CD40. Nat. Med. 5:780-787. doi:10.1038/10503
72. Steinman, R.M., and J. Banchereau. 2007. Taking dendritic cells into medicine. Nature. 449:419-426. doi:10.1038/nature06175
73. Stephan, M.T., V. Ponomarev, R.J. Brentjens, A.H. Chang, K.V. Dobrenkov, G. Heller, and M. Sadelain. 2007. T cellen-coded CD80 and 4-1BBL induce auto- and transcostimulation, resulting in potent tumor rejection. Nat. Med. 13:1440-1449. doi:10.1038/nm1676
74. + regulatory T cells in antitumor therapy reveals alternative pathways for suppression of autoreactive cytotoxic T lymphocyte responses. J. Exp. Med. 194:823-832. doi:10.1084/jem.194.6.823
75. Tamada, K., and L. Chen. 2006. Renewed interest in cancer immunotherapy with the tumor necrosis factor superfamily molecules. Cancer Immunol. Immunother. 55:355-362. doi:10.1007/s00262-005-0081-y
76. Terme, M., N. Chaput, B. Combadiere, A. Ma, T. Ohteki, and L. Zitvogel. 2008. Regulatory T cells control dendritic cell/NK cell cross-talk in lymph nodes at the steady state by inhibiting CD4+ self-reactive T cells. J. Immunol. 180:4679-4686.
77. Toes, R.E., F. Ossendorp, R. Offringa, and C.J. Melief. 1999. CD4 T cells and their role in antitumor immune responses. J. Exp. Med. 189:753-756. doi:10.1084/jem.189.5.753
78. Vence, L., A.K. Palucka, J.W. Fay, T. Ito, Y.J. Liu, J. Banchereau, and H. Ueno. 2007. Circulating tumor antigen-specific regulatory T cells in patients with metastatic melanoma. Proc. Natl. Acad. Sci. USA. 104: 20884-20889. doi:10.1073/pnas.0710557105
79. Wang, R.F. 2001. The role of MHC class II-restricted tumor antigens and CD4+ T cells in antitumor immunity. Trends Immunol. 22:269-276. doi:10.1016/S1471-4906(01)01896-8
80. Weaver, C.T., and A.Y. Rudensky. 2009. Editorial overview: lymphocyte development. Curr. Opin. Immunol. 21:119-120. doi:10.1016/j.coi.2009.03. 007
81. Wilcox, R.A., D.B. Flies, G. Zhu, A.J. Johnson, K. Tamada, A.I. Chapoval, S.E. Strome, L.R. Pease, and L. Chen. 2002. Provision of antigen and CD137 signaling breaks immunological ignorance, promoting regression of poorly immunogenic tumors. J. Clin. Invest. 109:651-659.
82. Williams, M.A., A.J. Tyznik, and M.J. Bevan. 2006. Interleukin-2 signals during priming are required for secondary expansion of CD8+ memory T cells. Nature. 441:890-893. doi:10.1038/nature04790
83. Wrzesinski, C., C.M. Paulos, L. Gattinoni, D.C. Palmer, A. Kaiser, Z. Yu, S.A. Rosenberg, and N.P. Restifo. 2007. Hematopoietic stem cells promote the expansion and function of adoptively transferred antitumor CD8 T cells. J. Clin. Invest. 117:492-501. doi:10.1172/JCI30414
84. Wuest, T., J. Farber, A. Luster, and D.J. Carr. 2006. CD4+ T cell migration into the cornea is reduced in CXCL9 deficient but not CXCL10 deficient mice following herpes simplex virus type 1 infection. Cell. Immunol. 243:83-89. doi:10.1016/j.cellimm.2007.01.001
85. Yu, P., Y. Lee, W. Liu, R.K. Chin, J. Wang, Y. Wang, A. Schietinger, M. Philip, H. Schreiber, and Y.X. Fu. 2004. Priming of naive T cells inside tumors leads to eradication of established tumors. Nat. Immunol. 5:141-149. doi:10.1038/ni1029
86. Zhang, H., K.S. Chua, M. Guimond, V. Kapoor, M.V. Brown, T.A. Fleisher, L.M. Long, D. Bernstein, B.J. Hill, D.C. Douek, et al. 2005. Lymphopenia and interleukin-2 therapy alter homeostasis of CD4+CD25+ regulatory T cells. Nat. Med. 11:1238-1243. doi:10.1038/nm1312