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 5

B cells limit effector CD8+ T cell expansion following mRNA LNP vaccination, preserving memory pool.

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B cells limit effector CD8+ T cell expansion following mRNA LNP vaccinat...
(A–E) Mice were given either a primary mRNA LNP vaccination only (left) or a primary vaccine followed by a booster 30 days later (right). (A) Experimental schematic. (B) Representative dual tetramer staining for CD44hi CD8+ T cells (left) and CD127 × TCF1 plots for tetramer+ cells after primary-only (middle) or primary-plus-boost (right) vaccination. (C) Spleens were assessed for the percentage of tetramer+CD127hi cells and tetramer+CD127lo cells out of total CD8+ T cells. (D) Percentage of TCF1+CD127hi cells within tetramer+ cells. (E) Percentage of tetramer+ cells positive for granzyme B. Data shown are means ± SEM, n = 5 mice per group, representative of 2 experiments. Significance was defined by t tests; **P < 0.01, ***P < 0.001. (F and G) Healthy control (HC) subjects or patients with MS receiving anti-CD20 antibody therapy were assessed for antigen-specific T cells 10–12 days after an mRNA LNP COVID-19 vaccine boost. (F) Experimental schematic. (G) Antigen-specific cells were quantified as the percentage of non-naive CD8+ T cells positive for the activation-induced markers (AIMs) 4-1BB and IFN-γ and divided into TCM (CD45RA−CD27+CCR7+), TEM (CD45RA−CD27−CCR7− plus CD45RA−CD27+CCR7−), and TEMRA (CD45RA+CD27−CCR7−) subsets (boxes, 25th–75th percentile; horizontal lines, median). Significance was defined by Mann Whitney tests; *P ≤ 0.05. (H–M) HC subjects or XLA patients were vaccinated, and blood was taken 6 months after the first vaccine dose for single-cell sequencing. (H) Experimental schematic. (I) UMAP visualization of AIM+ (4-1BB+CD69+) CD8+ T cells highlighting the cells from 6 months after vaccination. (J) Contour plots of CITE-Seq protein data for CD45RA and CCR7 from HC subjects (top) and XLA patients (bottom). (K) Percentages of TCM, TEM, and TEMRA were analyzed using 2-tailed Mann-Whitney tests; *P ≤ 0.05. (L) Violin plots of genes associated with cytotoxicity and memory. (M) Module scores for cytotoxicity and self-renewal gene signatures as box plots (vertical lines, minimum/maximum; boxes, 25th–75th percentile; horizontal lines, median) were analyzed using 2-tailed Mann-Whitney tests; **P < 0.01, ***P < 0.001.