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Cell-intrinsic Transforming Growth Factor-[beta] signaling mediates virus-specific CD8⁺ T cell deletion and lymphocytic choriomeningitis virus persistence in vivo


Chronic viral infections lead to a delicate long-term equilibrium between pathogen and host and represent a major biomedical problem for human populations worldwide. Although, in both humans and mice, viral persistence has been associated with insufficient numbers and/or dysfunction of effector CD8⁺ T cells, the underlying mechanisms involved in these pathogen evasion strategies are not completely understood. By using lymphocytic choriomeningitis virus (LCMV) infection in its natural murine host, we found that enhanced and sustained Transforming Growth Factor-[beta] (TGF-[beta]) expression and phosphorylation of its signaling mediator, Smad-2, were distinctive features of virus-specific CD8⁺ T cells during chronic versus acute viral infections in vivo. Selective attenuation of TGF-[beta] pathway in T cells decreased the expression of the pro-apoptotic protein Bim and increased survival and numbers of virus-specific CD8⁺ T cells. Under these conditions, virus-specific CD8⁺ T cells showed enhanced cytotoxicity, increased production of anti-viral cytokines, and down-regulation of the inhibitory molecules programmed-death-1 (PD-1) and interleukin-10 (IL-10). The presence of these enhanced numbers of functional virus-specific CD8⁺ T cells resulted in rapid virus eradication and generation of an effective memory T cell response that protected the host upon subsequent challenge. Notably, we found that cell- intrinsic TGF-[beta] signaling was responsible for virus- specific-CD8⁺ T cell apoptosis but was not necessary for their functional exhaustion. Our findings demonstrate that sustained TGF-[beta] -Smad signaling is as a hallmark and biologically meaningful regulator of CD8⁺ T cell responses during chronic viral infection in vivo

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