Mapping the lineage relationship between CXCR5+ and CXCR5- CD4+ T cells in HIV infected human lymph nodes

Summary CXCR5 is a key surface marker expressed on follicular helper T (T FH ) 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 T FH -like protein expression and function. CXCR5 - PD-1 + CD4 + T cells are related to T FH 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