Transient inhibition of type I interferon enhances CD8 T cell stemness and vaccine protection.

Unlabelled: 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 ) cells are important determinants of long-lived memory. Yet, the developmental requirements for T formation are unclear. Here, we identify the temporal window for type I interferon (IFN-I) receptor (IFNAR) blockade to drive T cell generation. T cells were transcriptionally distinct and emerged from a transitional precursor of exhausted (T ) cellular state concomitant with viral clearance. T 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 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 ) cell differentiation without establishing chronic infection. T and precursor of exhausted (T ) cellular states are distinguished transcriptionally and by cell surface markers. Developmentally, T cell differentiation occurs via a transition from a T state coinciding with viral clearance. Transient IFNAR blockade increases IFNψ production to modulate the ligands of CXCR3 and couple T differentiation to cell retention within the T cell paracortex of the lymph node. Specific promotion of T cell differentiation with nucleoside-modified mRNA-LNP vaccination elicits enhanced protection against chronic viral challenge.