TGF-β suppresses the activation of CD8⁺ T cells when naïve but promotes their survival and function once antigen-experienced: a two-faced impact on autoimmunity

Abstract

Objective: TGF-β can exhibit strong immune suppression but has also been shown to promote T cell growth. We investigated the differential effect of this cytokine on CD8⁺ T cells in autoimmunity and antiviral immunity.

Research Design and Methods: We used mouse models for virally induced type 1 diabetes (T1D) in conjunction with transgenic systems enabling manipulation of TGF-β expression or signaling in vivo.

Results: Surprisingly, when expressed selectively in the pancreas TGF-β reduced apoptosis of differentiated autoreactive CD8⁺ T cells, favoring their expansion and infiltration of the islets. These results pointed to drastically opposite roles of TGF-β on naïve compared antigen-experienced/memory CD8⁺ T cells. Indeed, in the absence of functional TGF-β signaling in T cells fast-onset T1D caused by activation of naïve CD8⁺ T cells occurred faster, while slow-onset disease depending on accumulation and activation of antigen-experienced/memory CD8⁺ T cells was decreased. TGF-β receptor-deficient CD8⁺ T cells showed enhanced activation and expansion after LCMV infection in vivo but were more prone to apoptosis once antigen-experienced and failed to survive as functional memory cells. In vitro, TGF-β suppressed naïve CD8⁺ T cell activation and IFN-γ production, whereas memory CD8⁺ T cells stimulated in the presence of TGF-β showed enhanced survival and increased production of IL-17 in conjunction with IFN-γ.

Conclusions: The effect of TGF-β on CD8⁺ T cells is dependent on their differentiation status and activation history. These results highlight a novel aspect of the pleiotropic nature of TGF-β and have implications for the design of immune therapies involving this cytokine.