IL-10-IL-21-STAT3 axis regulates memory CD8 T cell development (110.9)

Abstract

Abstract Developing memory CD8 T cells is a paramount goal of many vaccines that will fight infections and cancer. Many types of acute infections can generate robust memory T cells, and therefore there must be a mechanism for instilling memory cell properties into a small portion of the memory precursor effector CD8 T cells and “preserve” their potential to develop into memory cells. However, the signals and genetic pathways that govern this process remain poorly defined. Here we show that the IL-10-IL-21-STAT3 pathway was critical for memory CD8 T cell development after acute LCMV infection. Lack of either IL-10 and IL-21 or STAT3, virus-specific CD8 T cells retained terminal effector (TE) differentiation states and failed to mature into protective memory T cells that contained self-renewing central memory T cells. Expression of BCL-6 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. Next, we began to dissect the cellular sources of IL-10 and IL-21 and the temporal role of these cytokines in effector and memory CD8 T cell differentiation. This will advance our understanding of cellular mechanisms of memory CD8 T cell fate commitment and maintenance.