T follicular regulatory cells (Tfr) reduce proliferation and downregulate induction of costimulatory molecules on human Tfh and B cells

Abstract

Abstract Recently defined specialized subset of Treg expressing CXCR5+PD1+FoxP3+ termed as T follicular regulatory (Tfr) cells regulates T follicular helper (Tfh) mediated B cell high-affinity and isotype-switched antibody production. To date, much of our understanding of the suppression mechanism of Tfr cells has been obtained from animal studies. The mechanism of Tfr regulation of humoral immunity in humans is still understudied. Here, we used cells from human mesenteric lymph nodes to study how Tfr affect Tfh and B cells and what specific Tfr-induced changes occur on Tfh and B cells in vitro. We report that Tfr suppress both Tfh and B cell function and proliferation in a dose dependent manner. We find that Tfr downregulate CD40, CD80/CD86 and CD38 on B cells and CD28, OX40, ICOS and CD38 on Tfh cells. We also show that blocking immune checkpoint receptors inhibits Tfr suppression of Tfh and B cells and partially restores the Tfh mediated B cell antibody production. These findings reveal that Tfr regulate activation of Tfh and B cells by downregulating key costimulatory receptors and ligands that help induce activation in both Tfh and B cells. These changes ultimately lead to decreased proliferation of both B cells and Tfh and reduced production of immunoglobulin by B cells. This research was supported in part by NIH R01 and VA.