Transforming Growth Factor-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

OBJECTIVE—Transforming growth factor-β (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 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 with antigen-experienced/memory CD8(+) T-cells. Indeed, in the absence of functional TGF-β signaling in T-cells, fast-onset type 1 diabetes caused by activation of naïve CD8(+) T-cells occurred faster, whereas 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 lymphocytic choriomeningitis virus 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 γ-interferon production, whereas memory CD8(+) T-cells stimulated in the presence of TGF-β showed enhanced survival and increased production of interleukin-17 in conjunction with γ-interferon. 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.