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

Broomfield, B. J.; Tan, C. W.; Qin, R. Z.; Duckworth, B. C.; Alvarado, C.; Dalit, L.; Chen, J.; Mackiewicz, L.; Muramatsu, H.; Pellegrini, M.; Rogers, K.; Moon, W. J.; Nutt, S. L.; Davis, M. J.; Pardi, N.; Wimmer, V.; Groom, J. R.

doi:10.1101/2024.06.26.600763

bioRxiv · 10.1101/2024.06.26.600763

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

Broomfield, B. J.·Tan, C. W.·Qin, R. Z.·Duckworth, B. C.·Alvarado, C.·Dalit, L.·Chen, J.·Mackiewicz, L.·Muramatsu, H.·Pellegrini, M.·Rogers, K.·Moon, W. J.·Nutt, S. L.·Davis, M. J.·Pardi, N.·Wimmer, V.·Groom, J. R.

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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 (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 IFN{psi}, 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. HIGHLIGHTSO_LIEarly, 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. C_LIO_LITSCM and precursor of exhausted (TPEX) cellular states are distinguished transcriptionally and by cell surface markers. C_LIO_LIDevelopmentally, TSCM cell differentiation occurs via a transition from a TPEX state coinciding with viral clearance. C_LIO_LITransient IFNAR blockade increases IFN{psi} production to modulate the ligands of CXCR3 and couple TSCM differentiation to cell retention within the T cell paracortex of the lymph node. C_LIO_LISpecific promotion of TSCM cell differentiation with nucleoside-modified mRNA-LNP vaccination elicits enhanced protection against chronic viral challenge. C_LI

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Broomfield, B. J., Tan, C. W., Qin, R. Z., Duckworth, B. C., Alvarado, C., Dalit, L., Chen, J., Mackiewicz, L., Muramatsu, H., Pellegrini, M., Rogers, K., Moon, W. J., Nutt, S. L., Davis, M. J., Pardi, N., Wimmer, V., Groom, J. R.. 2024-06-28. Transient inhibition of type I interferon enhances CD8+ T cell stemness and vaccine protection. https://doi.org/10.1101/2024.06.26.600763

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