Mapping the Lineage Relationship between CXCR5⁺ and CXCR5^- CD4⁺ T Cells in HIV-Infected Human Lymph Nodes

CXCR5 is a key marker of follicular helper T (T_FH) cells. Using primary lymph nodes (LNs) from HIV-infected patients, we identified a population of CXCR5^- CD4⁺ T cells with T_FH-cell-like features. This CXCR5^- subset becomes expanded in severe HIV infection and is characterized by the upregulation of activation markers and high PD-1 and ICOS surface expression. Integrated analyses on the phenotypic heterogeneity, functional capacity, T cell receptor (TCR) repertoire, transcriptional profile, and epigenetic state of CXCR5^-PD-1⁺ICOS⁺ T cells revealed a shared clonal relationship with T_FH cells. CXCR5^-PD-1⁺ICOS⁺ T cells retained a poised state for CXCR5 expression and exhibited a migratory transcriptional program. TCR sequence overlap revealed a contribution of LN-derived CXCR5^-PD-1⁺ICOS⁺ T cells to circulating CXCR5^- CD4⁺ T cells with B cell help function. These data link LN pathology to circulating T cells and expand the current understanding on the diversity of T cells that regulate B cell responses during chronic inflammation.