| First Author | Khattar M | Year | 2014 |
| Journal | PLoS One | Volume | 9 |
| Issue | 1 | Pages | e85882 |
| PubMed ID | 24416451 | Mgi Jnum | J:264945 |
| Mgi Id | MGI:6198875 | Doi | 10.1371/journal.pone.0085882 |
| Citation | Khattar M, et al. (2014) Interleukin-21 is a critical regulator of CD4 and CD8 T cell survival during priming under Interleukin-2 deprivation conditions. PLoS One 9(1):e85882 |
| abstractText | Optimal T cell activation and expansion require binding of the common gamma-chain (gammac) cytokine Interleukin-2 (IL-2) to its cognate receptor that in turn engages a gammac/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 gammac 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 gammac 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. |
