MAPK-activated protein kinase 2 orchestrates memory T-cell inflation in cytomegalovirus infection.

Memory T-cell inflation is a distinctive immunological phenomenon observed during persistent viral infections such as cytomegalovirus (CMV). Unlike conventional memory T-cell responses, which contract after infection resolution, a subset of CMV-specific T cells undergoes a progressive and sustained expansion, termed "inflation", which is thought to be critical for long-term immune surveillance. The molecular mechanisms that govern memory T-cell inflation remain incompletely understood, yet they are pivotal for understanding immune persistence and designing strategies against chronic viral infections. In this study, we investigated the role of MAPK-activated protein kinase 2 (MK2), a key downstream effector of p38 MAPK signaling, in regulating T-cell responses during murine CMV (MCMV) infection. Using MK2 knockout (MK2-KO) mice, we demonstrate that MK2 deficiency alters the dynamics of MCMV-specific CD8+ T-cell responses without impairing viral control or tissue replication. MK2 deficiency led to a reduction in noninflationary MCMV-specific CD8+ T cells during acute infection, followed by enhanced expansion of inflationary CD8+ T-cell subsets during latent infection. Furthermore, MK2-KO mice exhibited impaired effector differentiation, as evidenced by decreased expression of the terminal differentiation marker KLRG1 on MCMV-specific CD8+ T cells. Collectively, these findings identify MK2 as an important regulator of CD8+ T-cell magnitude, kinetics, and phenotype during both acute and latent MCMV infection. By demonstrating a role of MK2 in the regulation of memory T-cell inflation, this study provides new mechanistic insight into immune regulation with implications for vaccination, chronic infection, and immune aging.