AUTHOR=He Chenfeng , Malone Michael J. , Wendel Ben S. , Ma Ke-Yue , Del Alcazar Daniel , Weiner David B. , De Jager Philip L. , Del Río-Estrada Perla M. , Ablanedo-Terrazas Yuria , Reyes-Terán Gustavo , Su Laura F. , Jiang Ning 

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

JOURNAL=Frontiers in Immunology

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.859070

DOI=10.3389/fimmu.2022.859070

ISSN=1664-3224

ABSTRACT=<p>Follicular-helper T cells (T<sub>FH</sub>) are an essential arm of the adaptive immune system. Although T<sub>FH</sub> 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<sub>FH</sub> 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<sub>FH</sub> receiving attention in chronic infection are CXCR3-expressing T<sub>FH</sub> cells (CXCR3<sup>+</sup>T<sub>FH</sub>) due to their abnormal accumulation in secondary lymphoid tissues. Their function and clonal relationship with other T<sub>FH</sub> subsets in lymphoid tissues during infection, however, remains largely unclear. We thus systematically investigated this and other subsets of T<sub>FH</sub> 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<sup>+</sup>T<sub>FH</sub> compartment during HIV infection that correlates with a lower HIV burden. Deeper analysis into this population revealed a functional shift of CXCR3<sup>+</sup>T<sub>FH</sub> away from germinal center T<sub>FH</sub> (GC-T<sub>FH</sub>), including the altered expression of several important transcription factors and cytokines. CXCR3<sup>+</sup>T<sub>FH</sub> also upregulated cell migration transcriptional programs and were clonally related to peripheral T<sub>FH</sub> populations. In combination, these data suggest that CXCR3<sup>+</sup>T<sub>FH</sub> have a greater tendency to enter circulation than their CXCR3<sup>-</sup> counterparts, potentially functioning through distinct modalities that may lead to enhanced defense.</p>