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

• DOI: 10.1016/j.celrep.2019.08.037
• Publication Date: 2019-09-17T10:48:51Z
• Authors: Daniel Del Alcazar; Yifeng Wang; Chenfeng He; Ben S. Wendel; Perla M. Del Río-...; Jerome Lin; Yuria Ablanedo-Te...; Michael J. Malone; Stefany M. Hernandez; Ian Frank; Ali Naji; Gustavo Reyes-Terán; Ning Jiang; Laura F. Su
• Keywords: CD4-Positive T-Lymphocytes; Male; Receptors, CXCR5; 0301 basic medicine; B-Lymphocytes; 0303 health sciences; QH301-705.5; HIV Infections; Article; 3. Good health; 03 medical and health sciences; HIV-1; Humans; Female; Lymph Nodes; Biology (General)

SummaryCXCR5 is a key surface marker expressed on follicular helper T (TFH) cells. We report here B cell help functionality in a population of CD4+ T cells isolated from primary human lymph nodes (LN) that lacked CXCR5 expression. This CXCR5- subset is distinguished from other CXCR5- CD4+ T cells by high PD-1 expression. Accumulation of CXCR5-PD-1+ T cells correlated with peripheral CD4+ T cell depletion and an increase in T-bet+ B cells in the LN, highlighting these atypical CD4+ T cells as a key component of lymphoid dysregulation during chronic HIV infection. By interrogating the phenotypic heterogeneity, functional capacity, TCR repertoire, transcriptional profile, and epigenetic state of CXCR5-PD-1+ T cells, we showed that CXCR5-PD-1+ T cells are related to CXCR5+PD-1+ T cells and provided evidence for the down regulation of CXCR5 following cell division as one mechanism for the absence of CXCR5 expression. Notably, CXCR5-PD-1+ T cells exhibited a migratory transcriptional program and contributed to circulating CXCR5-PD-1+ T cells with B cell help functionality in the peripheral blood. Thus, these data link LN pathology to circulating T cells and expand the current understanding on T cell diversity in the regulation of B cell responses during chronic inflammation.High dimensional profiling of activated CD4+ T cells in HIV infected lymph nodes revealed an accumulation of a CXCR5 negative subset.CXCR5-PD-1+CD4+ T cells exhibited TFH-like protein expression and function.CXCR5-PD-1+CD4+ T cells are related to TFH cells by clonal lineage and epigenetic similarity.CXCR5-PD-1+CD4+ T cells upregulate a migratory gene program and contribute to circulating T cells with B cell help functionality