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.
Highlights
T cells play a central role in cell mediated immune responses to foreign antigens via recognition through their T cell receptors (TCR)
The cultured CD8+ T cells displayed reduced Bcl-2 expression, whereas CD4+ T cells maintained their steady levels even in the absence of IL-2 (Fig. 1C). These early events may correlate with the level of mitochondrial polarization [43], as successful T cell activation was associated with hyper-polarization of mitochondria, whereas initiation of T cell apoptosis was associated with mitochondrial depolarization [44]
Lack of IL-2 signaling in activated CD8+ T cells resulted in dramatic depolarization of mitochondrial membrane potential, whereas CD4+ T cells consistently maintained a hyper-polarized state of mitochondria under the same conditions (Fig. 1D)
Summary
T cells play a central role in cell mediated immune responses to foreign antigens via recognition through their T cell receptors (TCR). Because of its critical role in driving effector and memory T cell survival, proliferation and differentiation as well as its exclusive transient expression in antigen-activated T cells, IL-2 has been considered as a potential therapeutic target for modulating the immune response. Further studies using IL-2 and IL-2R deficient mice reconstituted with functional Tregs have revealed that expansion of activated T cells can occur without IL-2 signaling [4,32] What accounts for this IL-2 independent function of T cells is not yet established and there is a clear need to investigate the critical growth factors that promote the survival and function of activated T cells under IL-2 deprived conditions. Whether IL-21 plays a role in promoting the survival of T cells during the early events of priming under IL-2 deprivation is currently unknown Addressing these questions will improve our understanding of the cytokine signaling in T cell mediated immune responses and will assist in designing better immune therapies. These results suggest alternate patterns of cytokine signaling to promote T cell survival and function in the absence of IL-2
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