Transcriptome and TCR Repertoire Measurements of CXCR3⁺ T Follicular Helper Cells Within HIV-Infected Human Lymph...

Follicular-helper T cells (T_FH) are an essential arm of the adaptive immune system. Although T_FH were first discovered through their ability to contribute to antibody affinity maturation through co-stimulatory interactions with B cells, new light has been shed on their ability to remain a complex and functionally plastic cell type. Due to a lack sample availability, however, many studies have been limited to characterizing T_FH in mice or non-canonical tissue types, such as peripheral blood. Such constraints have resulted in a limited, and sometimes contradictory, understanding of this fundamental cell type. One subset of T_FH receiving attention in chronic infection are CXCR3-expressing T_FH cells (CXCR3⁺T_FH) due to their abnormal accumulation in secondary lymphoid tissues. Their function and clonal relationship with other T_FH subsets in lymphoid tissues during infection, however, remains largely unclear. We thus systematically investigated this and other subsets of T_FH within untreated HIV-infected human lymph nodes using Mass CyTOF and a combination of RNA and TCR repertoire sequencing. We show an inflation of the CXCR3⁺T_FH compartment during HIV infection that correlates with a lower HIV burden. Deeper analysis into this population revealed a functional shift of CXCR3⁺T_FH away from germinal center T_FH (GC-T_FH), including the altered expression of several important transcription factors and cytokines. CXCR3⁺T_FH also upregulated cell migration transcriptional programs and were clonally related to peripheral T_FH populations. In combination, these data suggest that CXCR3⁺T_FH have a greater tendency to enter circulation than their CXCR3^- counterparts, potentially functioning through distinct modalities that may lead to enhanced defense.