BioProject

Chronic infection and cancer are associated with suppressed T cell responses in the presence of activating antigen. More...

Chronic infection and cancer are associated with suppressed T cell responses in the presence of activating antigen. Recent work identified memory-like CD8+ T cells termed follicular cytotoxic T cells (TFC) which sustain T cell responses during persistent infection and are essential for the T-cell proliferative burst following PD1 blockade. Approaches to expand these cells are sought. We show that blockade of interferon type 1 (IFN-I) receptor leads to TFC 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-high cells to sustain proliferation and prevents premature cell cycle exit and programmed cell death. Transcriptome analysis revealed an IL-27-regulated gene module controlling survival of activated CD8+ T cells which is enhanced in IFNAR-attenuated conditions. We further demonstrated a cell-intrinsic requirement for the IL-27 target IRF1 in TFC expansion through promoting sustained division. These findings reveal that IL-27 opposes IFN-I to uncouple cell division from effector differentiation, and suggest IL-27 signaling could be exploited to augment self-renewing T cell populations in patients with chronic infections. Overall design: Cells were isolated from mouse spleens, sorted using flow cytometry and RNA isolated for sequencing. 3 replicates per biological group were used, each sample represents cells from an individual mouse. Less...