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

Broomfield, BJ; MURAMATSU, H; Tan, CW; Qin, RZ; Abberger, H; Duckworth, BC; Alvarado, C; Dalit, L; Lee, CL; Shandre Mugan, R; Mazrad, ZAI; Mackiewicz, L; Williams, BE; Chen, J; Takanashi, A; Fabb, S; Pellegrini, M; Rogers, KL; Moon, WJ; Pouton, CW; Davis, MJ; Nutt, SL; Pardi, N; Wimmer, VC; Groom, JR

Author(s): Broomfield, BJ; MURAMATSU, H; Tan, CW; Qin, RZ; Abberger, H; Duckworth, BC; Alvarado, C; Dalit, L; Lee, CL; Shandre Mugan, R; Mazrad, ZAI; Mackiewicz, L; Williams, BE; Chen, J; Takanashi, A; Fabb, S; Pellegrini, M; Rogers, KL; Moon, WJ; Pouton, CW; Davis, MJ; Nutt, SL; Pardi, N; Wimmer, VC; Groom, JR;
Details: Publication Year 2025-05-05,Volume 222,Issue #5,Page e20241148
Journal Title: Journal of Experimental Medicine
Abstract: Developing vaccines that promote CD8+ T cell memory is a challenge for infectious disease and cancer immunotherapy. TCF-1+ stem cell-like memory CD8+ T (TSCM) cells are important determinants of long-lived memory. Yet, the developmental requirements for TSCM cell formation are unclear. Here, we identify the temporal window for type I interferon receptor (IFNAR) blockade to drive TSCM cell generation following viral infection and mRNA-lipid nanoparticle vaccination. We reveal a reversible developmental trajectory where transcriptionally distinct TSCM cells emerged from a transitional precursor of exhausted T cellular state concomitant with viral clearance. TSCM cell differentiation correlated with T cell retention within the lymph node paracortex due to disrupted CXCR3 chemokine gradient formation. These effects were linked to increased antigen load and a counterintuitive increase in IFNγ, which controlled cell location. Vaccination with the IFNAR blockade promoted TSCM cell differentiation and enhanced protection against chronic infection. These findings propose an approach to vaccine design whereby modulation of inflammation promotes memory formation and function.
Keywords: Animals; *CD8-Positive T-Lymphocytes/immunology; *Receptor, Interferon alpha-beta/metabolism/genetics; Mice; *Interferon Type I/metabolism/immunology; *Immunologic Memory; *Mice, Inbred C57BL; *Cell Differentiation/immunology; *Receptors, CXCR3/metabolism; Interferon-gamma/metabolism/immunology; Hepatocyte Nuclear Factor 1-alpha/metabolism; Memory T Cells/immunology/metabolism; Stem Cells/immunology/metabolism; Vaccination; Female
Research Division(s): Immunology; Bioinformatics and Computational Biology; Infection and Global Health; Advanced Technology and Biology; Personalised Oncology
PubMed ID: 40062995
Publisher's Version: https://doi.org/10.1084/jem.20241148
Open Access at Publisher's Site: https://doi.org/10.1084/jem.20241148
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2025-03-19 09:29:38

Last Modified: 2025-04-08 03:12:58