CD9 identifies and regulates a highly functional and unique subset of T follicular helper (Tfh) cells necessary for the promotion of antibodies during infection

Abstract

Abstract T follicular helper (Tfh) cells comprise a subset of CD4 +T helper (Th) cells phenotypically and functionally distinct from Th1 and Th2 cell subsets. Tfh cells are located within B cell follicles and germinal centers (GC), where they secrete the cytokines IL-21 and interferon-γ (IFN-γ) which aid in B cell proliferation and differentiation. CD9, a tetraspanin, has been shown to accumulate on CD4 T cells at the immunological synapse, playing a role in co-stimulation and stabilization of the synapse via regulation of the integrins LFA-1 and VLA-4. CD9 has been shown to be expressed on activated CD4 T cells, but whether it remains upregulated specifically on Tfh cells is unknown. We identified a distinct population of CD9-expressing Tfh cells (CD9 hi) following acute viral infections and examined their role in promoting GC responses. Following acute LCMV infection, CD9 hiTfh cells are found in the follicles and GCs, yet exhibited enhanced proliferation and migratory capacity to the chemokines CXCL12 and CXCL13. Epigenetically, CD9 hiTfh cells demonstrated a distinct transcriptional profile and chromatin architecture from their CD9 locounterpart, with an upregulation of cell cycling, PI3K, and integrin-regulated genes. Functionally, CD9 hiTfh cells had elevated VLA-4 expression and were the predominant producers of IL-21 and IFN-γ, indicating a specific role in B cell maturation and differentiation. Furthermore, deletion of CD9 did not alter Tfh cell development, but lead to their reduction of IL-21 and IFN-γ production and a decrease in overall antibody responses. Therefore, we identified that CD9 hiTfh cells are a highly functional and unique subset necessary for the promotion of antibodies during infection. R01 AR073912