Human T follicular regulatory cells (Tfr) able to inhibit antibody production are enriched at the lymph node T-B border and rare in germinal centers

Abstract

Abstract T follicular helper (Tfh) cells are a subset of CD4+ T cells that are critical for the formation of germinal centers (GCs) and the development of high affinity, class-switched antibodies. Tfh cells are differentiated in a Bcl6-dependent manner and are characterized by expression of the inhibitory receptor PD-1 along with CXCR5, a chemokine receptor that directs these cells to the follicle. More recently, T follicular regulatory cells (Tfr) have been shown to express regulatory T cell (Treg) markers and suppress humoral immunity. To date, much of our understanding of the function and distribution of Tfh and Tfr cells has been obtained from animal studies. Using highly multiplexed, quantitative imaging and functional assays, we examined the spatial distribution and suppressive function of human Tfr cells obtained from mesenteric lymph nodes. Here, we report that the majority of Tfr cells reside at the border between the T cell zone and B cell follicle and are rare within the GC, being far outnumbered by Tfh cells. In contrast to Tfh cells, Tfr cells expressed low to undetectable levels of PD-1 in situ yet potently suppressed antibody production in vitro. These findings reveal that Tfh and Tfr cells are spatially segregated within human lymph nodes and caution against using PD-1 expression levels as a phenotypic marker for human Tfr cells. This research was supported in part by NIH R01, VA, and Intramural Research Program of the NIH, NIAID.