Memory CD8+ T cells are critical for long-term immunity, but the genetic pathways governing their formation remain poorly defined. This study shows that the IL-10-IL-21-STAT3 pathway is critical for memory CD8+ T cell development after acute LCMV infection. In the absence of either interleukin-10 (IL-10) and IL-21 or STAT3, virus-specific CD8+ T cells retain terminal effector (TE) differentiation states and fail to mature into protective memory T cells that contain self-renewing central memory T cells. Expression of Eomes, BCL-6, Blimp-1, and SOCS3 was considerably reduced in STAT3-deficient memory CD8+ T cells, and BCL-6- or SOCS3-deficient CD8+ T cells also had perturbed memory cell development. Reduced SOCS3 expression rendered STAT3-deficient CD8+ T cells hyperresponsive to IL-12, suggesting that the STAT3-SOCS3 pathway helps to insulate memory precursor cells from inflammatory cytokines that drive TE differentiation. Thus, memory CD8+ T cell precursor maturation is an active process dependent on IL-10-IL-21-STAT3 signaling.
Graphical Abstract
Highlights
► STAT3 promotes formation of mature, self-renewing, protective memory CD8 T cells ► IL-10+IL-21, via STAT3, enhance persistence of memory precursor cells (MPCs) ► STAT3 sustains expression of BCL-6, Eomes, and SOCS3 in memory CD8 T cells ► SOCS3 tempers STAT4 signaling in CD8 T cells and aides in MPC persistence