p38 signaling enhances short-lived effector cell differentiation and weakens central memory CD8+ T-cell formation

Abstract Memory CD8+ T cells are essential for long-term protective immunity. Here, we show that activation of p38 MAPK during the primary response of CD8+ T cells orchestrates a delicate balance between the formation of short-lived effector cells and memory precursor effector cells. p38αfl/flp38βfl/flGzmBcre/− mice, in which p38α and p38β were efficiently deleted in CD8+ T cells and also in early stages of T-cell development, were used in studying the role of the p38 pathway in T cells. The deletion of p38α and p38β (simplified as p38α/β) has very minor effects on thymic and peripheral T-cell development. In contrast, p38α/β-deficient CD8+ T cells were skewed toward a central memory phenotype and mounted stronger recall responses upon secondary challenge. Transcriptomic analyses of antigen-specific CD8+ T cells revealed that p38α/β deficiency is associated with reduced effector gene expression and enhanced memory-associated programs. Furthermore, in vitro differentiated p38α/β-deficient CD8+ T cells showed superior persistence and functional responses after adoptive transfer. These results establish a role for p38 in controlling effector CD8+ T-cell differentiation and memory formation, and reinforce the therapeutic potential of targeting this pathway, aligning with recent studies demonstrating the beneficial effects of p38 inhibitors in adoptive cell therapy.