Cytokine-mediated regulation of immunity during persistent viral infection

T cell exhaustion is a state of T cell hypofunction arising during persistent viral infections and cancer. Recent advances in the field of immunology uncover the roles of cytokines in regulating T cell responses. Using LCMV Clone-13 as a model of persistent viral infection, this thesis investigates the roles of IL-27 and IFN-I in regulating T cells during infection. In addition, the thesis explores the potential of JAK inhibitor in rescuing T cell exhaustion during persistent viral infection and cancer. R01AI118862; R01AI123210LUMC / Geneeskund

IL-27 promotes the expansion of self-renewing CD8(+) T cells in persistent viral infection

Chronic infection and cancer are associated with suppressed T cell responses in the presence of cognate antigen. Recent work identified memory-like CXCR5(+) TCF1(+) CD8(+) T cells that sustain T cell responses during persistent infection and proliferate upon anti-PD1 treatment. Approaches to expand these cells are sought. We show that blockade of interferon type 1 (IFN-I) receptor leads to CXCR5(+) CD8(+) T cell expansion in an IL-27- and STAT1-dependent manner. IFNAR1 blockade promoted accelerated cell division and retention of TCF1 in virus-specific CD8(+) T cells. We found that CD8(+) T cell-intrinsic IL-27 signaling safeguards the ability of TCF1(hi) cells to maintain proliferation and avoid terminal differentiation or programmed cell death. Mechanistically, IL-27 endowed rapidly dividing cells with IRF1, a transcription factor that was required for sustained division in a cell-intrinsic manner. These findings reveal that IL-27 opposes IFN-I to uncouple effector differentiation from cell division and suggest that IL-27 signaling could be exploited to augment self-renewing T cells in chronic infections and cancer

Cytokine-mediated regulation of immunity during persistent viral infection

T cell exhaustion is a state of T cell hypofunction arising during persistent viral infections and cancer. Recent advances in the field of immunology uncover the roles of cytokines in regulating T cell responses. Using LCMV Clone-13 as a model of persistent viral infection, this thesis investigates the roles of IL-27 and IFN-I in regulating T cells during infection. In addition, the thesis explores the potential of JAK inhibitor in rescuing T cell exhaustion during persistent viral infection and cancer. </p