Abstract
Developing vaccines that promote CD8 (+) T cell memory is a challenge for infectious disease and cancer immunotherapy. TCF-1 (+) stem cell-like memory T (T (SCM) ) cells are important determinants of long-lived memory. Yet, the developmental requirements for T (SCM) formation are unclear. Here, we identify the temporal window for type I interferon (IFN-I) receptor (IFNAR) blockade to drive T (SCM) cell generation. T (SCM) cells were transcriptionally distinct and emerged from a transitional precursor of exhausted (T (PEX) ) cellular state concomitant with viral clearance. T (SCM) differentiation correlated with T cell retention within the lymph node paracortex, due to increased CXCR3 chemokine abundance which disrupted gradient formation. These affects were due a counterintuitive increase in IFNψ, which controlled cell location. Combining IFNAR inhibition with mRNA-LNP vaccination promoted specific T (SCM) differentiation and enhanced protection against chronic infection. These finding propose a new approach to vaccine design whereby modulation of inflammation promotes memory formation and function. HIGHLIGHTS: Early, transient inhibition of the type I interferon (IFN) receptor (IFNAR) during acute viral infection promotes stem cell-like memory T (T (SCM) ) cell differentiation without establishing chronic infection. T (SCM) and precursor of exhausted (T (PEX) ) cellular states are distinguished transcriptionally and by cell surface markers. Developmentally, T (SCM) cell differentiation occurs via a transition from a T (PEX) state coinciding with viral clearance. Transient IFNAR blockade increases IFNψ production to modulate the ligands of CXCR3 and couple T (SCM) differentiation to cell retention within the T cell paracortex of the lymph node. Specific promotion of T (SCM) cell differentiation with nucleoside-modified mRNA-LNP vaccination elicits enhanced protection against chronic viral challenge.