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

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.

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.