B cells shape naive CD8+ T cell programming
Cameron Manes, … , Ross M. Kedl, Jared Klarquist
Cameron Manes, … , Ross M. Kedl, Jared Klarquist
Published April 17, 2025
Citation Information: J Clin Invest. 2025;135(12):e190106. https://doi.org/10.1172/JCI190106.
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Research Article Autoimmunity Immunology

B cells shape naive CD8+ T cell programming

Abstract

The presence of B cells is essential for the formation of CD8+ T cell memory after infection and vaccination. In this study, we investigated whether B cells influence the programming of naive CD8+ T cells prior to their involvement in an immune response. RNA sequencing indicated that B cells are necessary for sustaining the FOXO1-controlled transcriptional program, which is critical for homeostasis of these T cells. Without an appropriate B cell repertoire, mouse naive CD8+ T cells exhibit a terminal, effector-skewed phenotype, which significantly impacts their response to vaccination. A similar effector-skewed phenotype with reduced FOXO1 expression was observed in naive CD8+ T cells from human patients undergoing B cell–depleting therapies. Furthermore, we show that patients without B cells have a defect in generating long-lived CD8+ T cell memory following COVID vaccination. In summary, we demonstrate that B cells promote the quiescence of naive CD8+ T cells, poising them to become memory cells upon vaccination.

Authors

Cameron Manes, Miguel Guerrero Moreno, Jennifer Cimons, Marc A. D’Antonio, Tonya M. Brunetti, Michael G. Harbell, Sean Selva, Christopher Mizenko, Tyler L. Borko, Erika L. Lasda, Jay R. Hesselberth, Elena W.Y. Hsieh, Michael R. Verneris, Amanda L. Piquet, Laurent Gapin, Ross M. Kedl, Jared Klarquist

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Figure 1

B cells promote memory-fated CD8+ T cell responses to vaccination and infection.

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B cells promote memory-fated CD8+ T cell responses to vaccination and in...
(A–J) WT or MD4 mice were either vaccinated with a combined-adjuvant subunit vaccine or infected with vaccinia virus (VV) or LCMV. (A) Experimental schematic. (B) Representative tetramer staining for pre-gated on live, CD19−CD8+ lymphocytes. (C) Histograms showing CD127 expression by tetramer+ cells. Naive (CD44lo) CD8+ T cells from WT mice provide a high CD127 reference for the LCMV histograms. (D–F) Seven days after vaccination, spleens were assessed for number (D) and percentage (E) of SIINFEKL tetramer+ cells, and CD127 geometric mean fluorescence intensity (gMFI) for tetramer+CD127hi cells (F). (G and H) Seven days after VV infection, spleens were assessed for number (G) and percentage (H) of B8R tetramer+ cells. (I and J) Eight days after LCMV-Armstrong infection, spleens were assessed for number (I) and percentage (J) of GP33 tetramer+ cells. (K–T) Sublethally irradiated WT or MD4 mice received 1 million CAR or control T cells. After 30 days, mice were vaccinated with the combined-adjuvant subunit vaccine. (K) Experimental schematic. (L) PBMCs were assessed for B cells (CD19+) and CAR T cells (TCRβ+CD45.1+hEGFR+). (M) B cell frequencies (left) and CAR T cell frequencies (right). (N–T) Seven days after vaccination, spleens were assessed for relative abundance of splenic tetramer+ CD127hi cells and CD127lo cells (N and O); tetramer+ cells were assessed for CD127 gMFI (P), FOXO1 gMFI (Q), percentage positive for TCF1 (R), percentage positive for granzyme B (S), and IRF4 gMFI (T). Data shown are means ± SEM, n = 4–5 mice per group, representative of 2 experiments. Significance was defined by 2-way ANOVA (D, E, and N–T) or 1-way ANOVA (F) with Holm-Šidák multiple-comparison test; *P < 0.05, **P < 0.01, ***P < 0.001.