MAPKAP Kinase 2 Orchestrates Memory T Cell Inflation in Cytomegalovirus Infection

Abstract

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 investigate the role of MAP kinase-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 non-inflationary MCMV-specific CD8 T cells during the acute phase, followed by enhanced expansion of inflationary CD8 T cell subsets during persistence. 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 a pivotal regulator of CD8 T cell magnitude, kinetics, and phenotype during both acute and chronic MCMV infection. By elucidating the 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. Graphical abstractThe graphical abstract was created using BioRender (https://biorender.com/). O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=120 SRC="FIGDIR/small/699974v1_ufig1.gif" ALT="Figure 1"> View larger version (34K): org.highwire.dtl.DTLVardef@140d602org.highwire.dtl.DTLVardef@1a23691org.highwire.dtl.DTLVardef@ac75b6org.highwire.dtl.DTLVardef@640d68_HPS_FORMAT_FIGEXP M_FIG C_FIG