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 (TSCM) cells are important determinants of long-lived memory. Yet, the developmental requirements for TSCM formation are unclear. Here, we identify the temporal window for type I interferon (IFN-I) receptor (IFNAR) blockade to drive TSCM cell generation. TSCM cells were transcriptionally distinct and emerged from a transitional precursor of exhausted (TPEX) cellular state concomitant with viral clearance. TSCM 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 IFNγ, which controlled cell location. Combining IFNAR inhibition with mRNA-LNP vaccination promoted specific TSCM 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.