Cutting Edge: Rapamycin Augments Pathogen-Specific but Not Graft-Reactive CD8+ T Cell Responses

Recent evidence demonstrating that exposure to rapamycin during viral infection increased the quantity and quality of Ag-specific T cells poses an intriguing paradox, because rapamycin is used in transplantation to dampen, rather than enhance, donor-reactive T cell responses. In this report, we compared the effects of rapamycin on the Ag-specific T cell response to a bacterial infection versus a transplant. Using a transgenic system in which the Ag and the responding T cell population were identical in both cases, we observed that treatment with rapamycin augmented the Ag-specific T cell response to a pathogen, whereas it failed to do so when the Ag was presented in the context of a transplant. These results suggest that the environment in which an Ag is presented alters the influence of rapamycin on Ag-specific T cell expansion and highlights a fundamental difference between Ag presented by an infectious agent as compared with an allograft.

[1]  Yoram Vodovotz,et al.  Mammalian Target of Rapamycin Inhibition and Alloantigen-Specific Regulatory T Cells Synergize To Promote Long-Term Graft Survival in Immunocompetent Recipients , 2009, The Journal of Immunology.

[2]  James McCluskey,et al.  T cell allorecognition via molecular mimicry. , 2009, Immunity.

[3]  W. Hörl,et al.  The Multifunctional Role of mTOR in Innate Immunity: Implications for Transplant Immunity , 2009, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[4]  R. Ahmed,et al.  mTOR regulates memory CD8 T cell differentiation , 2009, Nature.

[5]  A. Thomson,et al.  Immunoregulatory functions of mTOR inhibition , 2009, Nature Reviews Immunology.

[6]  B. Pulendran,et al.  Toll-like receptor–mediated induction of type I interferon in plasmacytoid dendritic cells requires the rapamycin-sensitive PI(3)K-mTOR-p70S6K pathway , 2008, Nature Immunology.

[7]  E. Wherry,et al.  MyD88 Plays a Critical T Cell-Intrinsic Role in Supporting CD8 T Cell Expansion during Acute Lymphocytic Choriomeningitis Virus Infection1 , 2008, The Journal of Immunology.

[8]  K. Shokat,et al.  T cell receptor signaling controls Foxp3 expression via PI3K, Akt, and mTOR , 2008, Proceedings of the National Academy of Sciences.

[9]  E. Ahmed,et al.  Prevention of Allograft Tolerance by Bacterial Infection with Listeria monocytogenes1 , 2008, The Journal of Immunology.

[10]  C. Benoist,et al.  The AKT–mTOR axis regulates de novo differentiation of CD4+Foxp3+ cells , 2008, The Journal of experimental medicine.

[11]  A. Mehrabi,et al.  Sirolimus in renal transplantation. , 2007, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[12]  Zhiliang Wang,et al.  Rapamycin-Conditioned Dendritic Cells Are Poor Stimulators of Allogeneic CD4+ T Cells, but Enrich for Antigen-Specific Foxp3+ T Regulatory Cells and Promote Organ Transplant Tolerance1 , 2007, The Journal of Immunology.

[13]  C. Larsen,et al.  Antigen-specific precursor frequency impacts T cell proliferation, differentiation, and requirement for costimulation , 2007, Journal of Experimental Medicine.

[14]  M. Hall,et al.  TOR Signaling in Growth and Metabolism , 2006, Cell.

[15]  E. Ingulli,et al.  Development of a Novel Transgenic Mouse for the Study of Interactions Between CD4 and CD8 T Cells During Graft Rejection , 2003, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[16]  Rustom Antia,et al.  Lineage relationship and protective immunity of memory CD8 T cell subsets , 2003, Nature Immunology.

[17]  E. Wherry,et al.  Heterologous immunity provides a potent barrier to transplantation tolerance. , 2003, The Journal of clinical investigation.

[18]  A. Valujskikh,et al.  T Cells Primed by Leishmania major Infection Cross-React with Alloantigens and Alter the Course of Allograft Rejection1 , 2002, The Journal of Immunology.

[19]  R. Ahmed,et al.  Recombinant Listeria monocytogenes as a live vaccine vehicle for the induction of protective anti-viral cell-mediated immunity. , 1995, Proceedings of the National Academy of Sciences of the United States of America.