title: Interleukin-21 is a critical regulator of CD4 and CD8 T cell survival during priming under Interleukin-2 deprivation conditions.
abstract: Optimal T cell activation and expansion require binding of the common gamma-chain (γc) cytokine Interleukin-2 (IL-2) to its cognate receptor that in turn engages a γc/Janus tyrosine kinase (Jak)3 signaling pathway. Because of its restricted expression by antigen-activated T cells and its obligatory role in promoting their survival and proliferation, IL-2 has been considered as a selective therapeutic target for preventing T cell mediated diseases. However, in order to further explore IL-2 targeted therapy, it is critical to precisely understand its role during early events of T cell activation. In this study, we delineate the role of IL-2 and other γc cytokines in promoting the survival of CD4 and CD8 T cells during early phases of priming. Under IL-2 inhibitory conditions (by neutralizing anti-IL-2 mAbs), the survival of activated CD8⁺ T cells was reduced, whereas CD4⁺ T cells remained much more resistant. These results correlated with reduced Bcl-2 expression, and mitochondrial membrane potential in CD8⁺ T cells in comparison to CD4⁺ T cells. However, using transwell co-culture assays we have found that CD4⁺ T cells could rescue the survival of CD8⁺ T cells even under IL-2 deprived conditions via secretion of soluble factors. A cytokine screen performed on CD8⁺ T cells cultured alone revealed that IL-21, another γc cytokine, was capable of rescuing their survival under IL-2 deprivation. Indeed, blocking the IL-21 signaling pathway along with IL-2 neutralization resulted in significantly reduced survival of both CD4⁺ and CD8⁺ T cells. Taken together, we have shown that under IL-2 deprivation conditions, IL-21 may act as the major survival factor promoting T cell immune responses. Thus, investigation of IL-2 targeted therapies may need to be revisited to consider blockade of the IL-21 signaling pathways as an adjunct to provide more effective control of T cell immune responses.
authors.affiliation: Department of Medical Microbiology and Immunology, University of Toledo College of Medicine, Toledo, Ohio, United States of America.
authors.forename: Mithun
authors.initials: M
authors.lastname: Khattar
authors.affiliation: Department of Medical Microbiology and Immunology, University of Toledo College of Medicine, Toledo, Ohio, United States of America.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Miyahara
authors.affiliation: Department of Medical Microbiology and Immunology, University of Toledo College of Medicine, Toledo, Ohio, United States of America.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Schroder
authors.affiliation: Transplant Immunology Center, Houston Methodist Research Institute, Houston, Texas, United States of America.
authors.forename: Aini
authors.initials: A
authors.lastname: Xie
authors.affiliation: Transplant Immunology Center, Houston Methodist Research Institute, Houston, Texas, United States of America.
authors.forename: Wenhao
authors.initials: W
authors.lastname: Chen
authors.affiliation: Department of Medical Microbiology and Immunology, University of Toledo College of Medicine, Toledo, Ohio, United States of America.
authors.forename: Stanislaw M
authors.initials: SM
authors.lastname: Stepkowski
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D018920:Coculture Techniques; D045142:Cross-Priming / Q000187:drug effects*; D007376:Interleukin-2 / Q000494:pharmacology*; D007378:Interleukins / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D000098546:Interleukin-21
chemical_list: D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D007376:Interleukin-2; D007378:Interleukins; D019253:Proto-Oncogene Proteins c-bcl-2; D000098546:Interleukin-21