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

Abstract

SUMMARYDeveloping vaccines that promote CD8+T cell memory is a challenge for infectious disease and cancer immunotherapy. TCF-1+stem cell-like memory T (TSCM) cells are important determinants of long-lived memory. Yet, the developmental requirements for TSCMformation are unclear. Here, we identify the temporal window for type I interferon (IFN-I) receptor (IFNAR) blockade to drive TSCMcell generation. TSCMcells were transcriptionally distinct and emerged from a transitional precursor of exhausted (TPEX) cellular state concomitant with viral clearance. TSCMdifferentiation 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 TSCMdifferentiation and enhanced protection against chronic infection. These finding propose a new approach to vaccine design whereby modulation of inflammation promotes memory formation and function.HIGHLIGHTSEarly, transient inhibition of the type I interferon (IFN) receptor (IFNAR) during acute viral infection promotes stem cell-like memory T (TSCM) cell differentiation without establishing chronic infection.TSCMand precursor of exhausted (TPEX) cellular states are distinguished transcriptionally and by cell surface markers.Developmentally, TSCMcell differentiation occurs via a transition from a TPEXstate coinciding with viral clearance.Transient IFNAR blockade increases IFNψ production to modulate the ligands of CXCR3 and couple TSCMdifferentiation to cell retention within the T cell paracortex of the lymph node.Specific promotion of TSCMcell differentiation with nucleoside-modified mRNA-LNP vaccination elicits enhanced protection against chronic viral challenge.