The inflammaging microenvironment induces dysfunctional rewiring of Tfh cell differentiation
Cody S. Nelson, … , Wayne A. Marasco, Peter T. Sage
Cody S. Nelson, … , Wayne A. Marasco, Peter T. Sage
Published March 4, 2025
Citation Information: JCI Insight. 2025;10(8):e187271. https://doi.org/10.1172/jci.insight.187271.
View: Text | PDF
Research Article Aging Immunology

The inflammaging microenvironment induces dysfunctional rewiring of Tfh cell differentiation

Abstract

Humoral immunity is orchestrated by follicular helper T (Tfh) cells, which promote cognate B cells to produce high-affinity, protective antibodies. In aged individuals, humoral immunity after vaccination is diminished despite the presence of Tfh cells, suggesting defects after initial Tfh cell formation. In this study, we utilized both murine and human systems to investigate how aging alters Tfh cell differentiation after influenza vaccination. We found that young Tfh cells underwent progressive differentiation after influenza vaccination, culminating in clonal expansion of effector-like cells in both draining lymph nodes and blood. In aging, early stages of Tfh cell development occurred normally. However, aging rewired the later stages of development in Tfh cells, resulting in a transcriptional program reflective of cellular senescence, sustained pro-inflammatory cytokine production, and metabolic reprogramming. We investigated the extent to which this rewiring of aged Tfh cells is due to the age-associated inflammatory (“inflammaging”) microenvironment and found that this setting was sufficient to both block the transition of Tfh cells to a post-effector resting state and skew Tfh cells toward the age-rewired state. Together, these data suggest that aging dampens humoral immunity by cytokine-mediated rewiring of late effector Tfh cell differentiation into an activated, yet less functional, cellular state.

Authors

Cody S. Nelson, Manuel A. Podestà, Maya G. Gempler, Jeong-Mi Lee, Cole J. Batty, Peterson G. Mathenge, Asra Sainju, Matthew R. Chang, Hanzhong Ke, Pragya Chandrakar, Elsa Bechu, Sierra Richardson, Cecilia B. Cavazzoni, Stefan G. Tullius, Reza Abdi, Musie Ghebremichael, Marcia C. Haigis, Wayne A. Marasco, Peter T. Sage

×

Figure 1

Expansion and clonal overlap of murine Tfh cells from LNs and blood after influenza vaccination.

Options: View larger image (or click on image) Download as PowerPoint
Expansion and clonal overlap of murine Tfh cells from LNs and blood afte...
(A) Experimental schematic. Wild-type mice (8–12 weeks of age) were administered the Afluria quadrivalent influenza vaccine (total 1.5 μg HA protein). After 10 days, CD4+CXCR5+ cells were sorted from both dLN and peripheral blood, and single-cell RNA sequencing (scRNA-Seq) with matched TCR-Seq was performed. (B–D) UMAPs of n = 6,752 cells by unsupervised cluster assignment (B), by tissue (C), and by cell type (D). (E) (Left) TCRβ-V and J gene usage. Percentage indicates frequency of use in dataset. (Right) Clonal sharing between the top 25 TCR clones by prevalence in LN and blood. Connecting lines indicate shared clones. (F) (Left) TCRβ V-J gene segment usage and (right) clonal sharing between Tfh and Tfr cells. (G) Clonal expansion (<0.01% “rare,” 0.01%–0.033% “small,” 0.033%–0.067% “medium,” 0.067%–0.1% “large,” and >0.1% “hyperexpanded”) for LN and blood cells. (H) TCR complementarity-determining region 3 amino acid sequence and predicted influenza specificity of the top 10 clones shared between LN and blood Tfh cells. Each clone is color coded. (I) TCRβ -V gene usage for clones in H. (J) UMAP of clones from H, including annotation of cluster 8 from B. (K) Module score for a Tfh Effector module (derived from ref. 14) expressed as a feature plot (left) or violin plot (right). Violin plot displays the Tfh Effector feature score 95% confidence interval for cells in indicated clusters, with the shape indicating the probability density and horizontal line denoting the median value. (L) (Left) Differential gene expression between cluster 8 and clusters 3, 4, 5, and 9 of the LN. (Right) Density plots for indicated genes. Data are from a single scRNA-Seq experiment of 2 individual mice concatenated.