Critical role for interleukin-21 in antiviral CD8-positive T lymphocyte responses

Cytokines of the common gamma chain (gammaC) family have been implicated in the generation and development of CD8 + T cell memory responses. The most recently identified member of this family of molecules IL-21 is produced by activated CD4+ T cells and is closely related to IL-2 and IL-15, two cytokines with particular importance in modulating CD8+ T cell responses. In this dissertation, we explore the role of IL-21 on CD8+ T cell responses to viruses.;To further explore the role of IL-21 as a regulator of CD8+ T cell responses to viral infections, we examined the kinetics and phenotypic profile of these cells in the IL-21Ralpha-/- mouse model. We observed that IL-21Ralpha-/- mice generate dramatically reduced primary and secondary CD8+ T cell responses specific for viral antigens. Interestingly, however, the memory cell-surface phenotype and cytokine profiles of these CD8+ T cells in IL-21Ralpha-/- mice do not differ from those of wildtype mice. We showed that IL-21R signals are necessary for the CD8+ T cells themselves to generate sufficient antiviral responses using mixed bone marrow chimeras. Our data indicate that IL-21 may be inducing proliferation and survival of these cells, potentially through reducing TRAIL expression. These data highlight a unique biology of IL-21 in modulating CD8+ T cell responses.;We first examined the ability of recombinant IL-21 to influence the growth and differentiation of antigen-specific CD8+ T cells in an in vitro culture system. We showed that recombinant human IL-21 can induce T cell proliferation and phosphorylation of STAT3. We also found that IL-21 can stimulate the proliferation and interferon-gamma secretion by cells responding to viral antigens. However, we observed that IL-21 has a unique ability to drive these cells to apoptosis, perhaps through the downregulation of Bcl-2 in these cell populations.