Regulation of antiviral CD8 T cell immunity by CD352/SLAMF6: from patterns to pathways

Abstract

Abstract A better understanding of CD8 memory T cell (TM) formation during acute and chronic viral infections is critical for both effective immunotherapy and vaccine design. Signaling lymphocytic activation molecule family receptors (SLAMF) including CD150, CD48, CD229, CD244, CD84, CD352, and CD319 were found to be involved in T cell activation and differentiation, but their contribution to the regulation of antigen-specific T cell immunity remains incompletely understood. Here, we analyzed the dynamics of SLAMF co-expression patterns by antiviral CD8 T cells in response to acute and chronic lymphocytic choriomeningitis virus (LCMV) infection. Our results demonstrate distinct SLAMF levels not only on LCMV-specific CD8 effector (TE) and TM cell subsets, but differential kinetics during acute vs. chronic infection. Importantly, we identified CD352 as a unique marker for long-term CD8 TM potential and capacity with significant upregulation on memory-precursor (MPEC) vs. short-lived effector (SLEC) as well as on central (TCM) vs. effector memory (TEM) CD8 T cells (MPEC>>TCM>TEM≥SLEC). Moreover, in the context of chronic viral infection, we found CD352+ CD8 T cells to be partially resistant to exhaustion as demonstrated by a memory-like phenotype, preserved CD8 T cell function, and better in vivo recall capacity upon adoptive transfer into naïve hosts. Conversely, chronically-infected CD352-deficient mice showed an impaired CD8 T cell response with reduced frequencies of LCMV-specific CD8 T cells, a more exhausted phenotype, lower expression of TM markers, and reduced functional properties. Collectively, our data reveal CD352 as a potential therapeutic target to modify CD8 T cell responses during acute and chronic viral infections.