This information is current as Occurring T Regulatory Cells T Helper Cells and Hindered by Naturally + Tumor/Self-Antigen Is Augmented by CD4 T Cell Immunity Against a + CD8

CD4 (cid:1) T cells control the effector function, memory, and maintenance of CD8 (cid:1) T cells. Paradoxically, we found that absence of CD4 (cid:1) T cells enhanced adoptive immunotherapy of cancer when using CD8 (cid:1) T cells directed against a persisting tumor/self-Ag. However, adoptive transfer of CD4 (cid:1) CD25 (cid:2) Th cells (Th cells) with tumor/self-reactive CD8 (cid:1) T cells and vaccination into CD4 (cid:1) T cell-deficient hosts induced autoimmunity and regression of established melanoma. Transfer of CD4 (cid:1) T cells that contained a mixture of Th and CD4 (cid:1) CD25 (cid:1) T regulatory cells (T reg cells) or T reg cells alone prevented effective adoptive immunotherapy. Maintenance of CD8 (cid:1) T cell numbers and function was dependent on Th cells that were capable of IL-2 production because therapy failed when Th cells were derived from IL-2 (cid:2) / (cid:2) mice. These findings reveal that Th cells can help break tolerance to a persisting self-Ag and treat established tumors through an IL-2-dependent mechanism, but requires simultaneous absence of naturally occurring T reg cells to be effective. The Journal of Immunology, 2005, 174: 2591–2601.

[1]  C. Klebanoff,et al.  Sinks, suppressors and antigen presenters: how lymphodepletion enhances T cell-mediated tumor immunotherapy. , 2005, Trends in immunology.

[2]  M. Noris,et al.  Natural versus adaptive regulatory T cells. , 2005, Contributions to nephrology.

[3]  M. A. Curotto de Lafaille,et al.  CD25− T Cells Generate CD25+Foxp3+ Regulatory T Cells by Peripheral Expansion1 , 2004, The Journal of Immunology.

[4]  T. Malek,et al.  Tolerance, not immunity, crucially depends on IL-2 , 2004, Nature Reviews Immunology.

[5]  S. Rutz,et al.  Interleukin‐2 is essential for CD4+CD25+ regulatory T cell function , 2004, European journal of immunology.

[6]  M. Bevan,et al.  CD4+ T cells are required for the maintenance, not programming, of memory CD8+ T cells after acute infection , 2004, Nature Immunology.

[7]  M. Bevan.  Helping the CD8+ T-cell response , 2004, Nature Reviews Immunology.

[8]  Ethan M. Shevach,et al.  Cutting Edge: IL-2 Is Critically Required for the In Vitro Activation of CD4+CD25+ T Cell Suppressor Function , 2004, The Journal of Immunology.

[9]  N. Sarvetnick,et al.  Homeostatic Expansion of T Cells during Immune Insufficiency Generates Autoimmunity , 2004, Cell.

[10]  S. Rosenberg.  clinical implications of basic research Shedding Light on Immunotherapy for Cancer , 2004 .

[11]  B. Nelson.  IL-2, Regulatory T Cells, and Tolerance , 2004, The Journal of Immunology.

[12]  S. Sakaguchi.  Naturally arising CD4+ regulatory t cells for immunologic self-tolerance and negative control of immune responses. , 2004, Annual review of immunology.

[13]  T. Waldmann,et al.  IL-15 enhances the in vivo antitumor activity of tumor-reactive CD8+ T Cells , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[14]  P. Musiani,et al.  IL-21 Induces Tumor Rejection by Specific CTL and IFN-γ-Dependent CXC Chemokines in Syngeneic Mice1 , 2004, The Journal of Immunology.

[15]  Youjin Lee,et al.  Priming of naive T cells inside tumors leads to eradication of established tumors , 2004, Nature Immunology.

[16]  A. Caton,et al.  Cutting Edge: Self-Peptides Drive the Peripheral Expansion of CD4+CD25+ Regulatory T Cells 1 , 2003, The Journal of Immunology.

[17]  D. Baltimore,et al.  Essential Role for STAT5 Signaling in CD25+CD4+ Regulatory T Cell Homeostasis and the Maintenance of Self-Tolerance1 , 2003, The Journal of Immunology.

[18]  D. Klatzmann,et al.  Continuous Activation of Autoreactive CD4+ CD25+ Regulatory T Cells in the Steady State , 2003, The Journal of experimental medicine.

[19]  S. Rosenberg,et al.  Tumor Regression and Autoimmunity after Reversal of a Functionally Tolerant State of Self-reactive CD8+ T Cells , 2003, The Journal of experimental medicine.

[20]  Anna Chodos,et al.  Antigen-dependent Proliferation of CD4+ CD25+ Regulatory T Cells In Vivo , 2003, The Journal of experimental medicine.

[21]  M. Bevan,et al.  Defective CD8 T Cell Memory Following Acute Infection Without CD4 T Cell Help , 2003, Science.

[22]  Urs Christen,et al.  CD4+ T cells are required for secondary expansion and memory in CD8+ T lymphocytes , 2003, Nature.

[23]  P. Greenberg,et al.  Adoptive therapy with CD8(+) T cells: it may get by with a little help from its friends. , 2002, The Journal of clinical investigation.

[24]  A. Freitas,et al.  Homeostasis of Peripheral CD4+ T Cells: IL-2Rα and IL-2 Shape a Population of Regulatory Cells That Controls CD4+ T Cell Numbers1 , 2002, The Journal of Immunology.

[25]  T. Elliott,et al.  Depletion of CD25+ regulatory cells uncovers immune responses to shared murine tumor rejection antigens , 2002, European journal of immunology.

[26]  M. Raffeld,et al.  Cancer Regression and Autoimmunity in Patients After Clonal Repopulation with Antitumor Lymphocytes , 2002, Science.

[27]  J. Lafaille,et al.  Interleukin 2 Signaling Is Required for CD4+ Regulatory T Cell Function , 2002, The Journal of experimental medicine.

[28]  B. Rocha,et al.  CD8 lethargy in the absence of CD4 help , 2002, European journal of immunology.

[29]  T. Malek,et al.  CD4 regulatory T cells prevent lethal autoimmunity in IL-2Rbeta-deficient mice. Implications for the nonredundant function of IL-2. , 2002, Immunity.

[30]  A. Theofilopoulos,et al.  T cell homeostatic proliferation elicits effective antitumor autoimmunity. , 2002, The Journal of clinical investigation.

[31]  L. Klein,et al.  Origin of regulatory T cells with known specificity for antigen , 2002, Nature Immunology.

[32]  J. Sprent,et al.  Interleukin (IL)-15 and IL-7 Jointly Regulate Homeostatic Proliferation of Memory Phenotype CD8+ Cells but Are Not Required for Memory Phenotype CD4+ Cells , 2002, The Journal of experimental medicine.

[33]  Ethan M. Shevach,et al.  Cutting Edge: Depletion of CD4+CD25+ Regulatory T Cells Is Necessary, But Not Sufficient, for Induction of Organ-Specific Autoimmune Disease , 2002, The Journal of Immunology.

[34]  Ethan M. Shevach,et al.  CD4+CD25+ suppressor T cells: more questions than answers , 2002, Nature Reviews Immunology.

[35]  N. Restifo,et al.  Do CD4+ CD25+ immunoregulatory T cells hinder tumor immunotherapy? , 2002, Journal of immunotherapy.

[36]  V. Cerundolo,et al.  Depletion of CD25+ regulatory cells results in suppression of melanoma growth and induction of autoreactivity in mice. , 2002, Cancer immunity.

[37]  G. Belz,et al.  Cutting Edge: Precursor Frequency Affects the Helper Dependence of Cytotoxic T Cells1 , 2002, The Journal of Immunology.

[38]  T. Schumacher,et al.  Synergism of Cytotoxic T Lymphocyte–Associated Antigen 4 Blockade and Depletion of Cd25+ Regulatory T Cells in Antitumor Therapy Reveals Alternative Pathways for Suppression of Autoreactive Cytotoxic T Lymphocyte Responses , 2001, The Journal of experimental medicine.

[39]  F. Foss.  Interleukin‐2 Fusion Toxin: Targeted Therapy for Cutaneous T Cell Lymphoma , 2001, Annals of the New York Academy of Sciences.

[40]  E. Gilboa.  The risk of autoimmunity associated with tumor immunotherapy , 2001, Nature Immunology.

[41]  E. Shevach,et al.  Cutting Edge: Control of CD8+ T Cell Activation by CD4+CD25+ Immunoregulatory Cells , 2001, The Journal of Immunology.

[42]  Steven A. Rosenberg,et al.  Progress in human tumour immunology and immunotherapy , 2001, Nature.

[43]  Rong Wang,et al.  The role of MHC class II-restricted tumor antigens and CD4+ T cells in antitumor immunity. , 2001, Trends in immunology.

[44]  B. Robinson,et al.  Tumor-Specific CD4+ T Cells Have a Major “Post-Licensing” Role in CTL Mediated Anti-Tumor Immunity1 , 2000, The Journal of Immunology.

[45]  R. Schreiber,et al.  Eradication of established tumors by CD8+ T cell adoptive immunotherapy. , 2000, Immunity.

[46]  H. Hall,et al.  CD4+CD25+ regulatory T cells down‐regulate co‐stimulatory molecules on antigen‐presenting cells , 2000, European journal of immunology.

[47]  N. Restifo,et al.  Autoimmunity and the immunotherapy of cancer: targeting the "self" to destroy the "other". , 2000, Critical reviews in immunology.

[48]  J. Shimizu,et al.  Induction of tumor immunity by removing CD25+CD4+ T cells: a common basis between tumor immunity and autoimmunity. , 1999, Journal of immunology.

[49]  A. Khoruts,et al.  CTLA-4 blockade reverses CD8+ T cell tolerance to tumor by a CD4+ T cell- and IL-2-dependent mechanism. , 1999, Immunity.

[50]  F. Otsuka,et al.  Thymus and autoimmunity: production of CD25+CD4+ naturally anergic and suppressive T cells as a key function of the thymus in maintaining immunologic self-tolerance. , 1999, Journal of immunology.

[51]  B. Moss,et al.  Vaccination with a recombinant vaccinia virus encoding a "self" antigen induces autoimmune vitiligo and tumor cell destruction in mice: requirement for CD4(+) T lymphocytes. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[52]  Ethan M. Shevach,et al.  CD4+CD25+ Immunoregulatory T Cells Suppress Polyclonal T Cell Activation In Vitro by Inhibiting Interleukin 2 Production , 1998, The Journal of experimental medicine.

[53]  C. Pénit,et al.  Regulatory Cd4 T Cells: Expression of Il-2rα Chain, Resistance to Clonal Deletion and Il-2 Dependency , 1998 .

[54]  E. Shevach,et al.  CD4+CD25+ T cells inhibit both the induction and effector function of autoreactive T cells and represent a unique lineage of immunoregulatory cells. , 1998, Journal of immunology.

[55]  C. Kurts,et al.  CD4+ T Cell Help Impairs CD8+ T Cell Deletion Induced by Cross-presentation of Self-Antigens and Favors Autoimmunity , 1997, Journal of Experimental Medicine.

[56]  C. Figdor,et al.  Cloning, expression and tissue distribution of the murine homologue of the melanocyte lineage-specific antigen gp100. , 1997, Melanoma research.

[57]  S. Sakaguchi,et al.  Autoimmune disease as a consequence of developmental abnormality of a T cell subpopulation , 1996, The Journal of experimental medicine.

[58]  Kendall A. Smith,et al.  Interleukin‐2 Deficient Mice: A New Model to Study Autoimmunity and Self‐Tolerance , 1995, Immunological reviews.

[59]  R. Ahmed,et al.  CD4+ T cells are required to sustain CD8+ cytotoxic T-cell responses during chronic viral infection , 1994, Journal of virology.

[60]  R. Zinkernagel,et al.  Immune responses in interleukin-2-deficient mice. , 1993, Science.

[61]  T. Waldmann,et al.  Interleukin 2 (IL-2) augments transcription of the IL-2 receptor gene. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[62]  R. North,et al.  T-cell-mediated suppression of anti-tumor immunity. An explanation for progressive growth of an immunogenic tumor , 1980, The Journal of experimental medicine.