T Cells That Help B Cells in Chronically Inflamed Tissues

Abstract

Chronically inflamed tissues commonly accrue lymphocyte aggregates that facilitate local T cell-B cell interactions. These aggregates can range from small, loosely arranged lymphocyte clusters to large, organized ectopic lymphoid structures. In some cases, ectopic lymphoid structures develop germinal centers that house prototypical T follicular helper (Tfh) cells with high expression of Bcl6, CXCR5, PD-1, and ICOS. However, in many chronically inflamed tissues, the T cells that interact with B cells show substantial differences from Tfh cells in their surface phenotypes, migratory capacity, and transcriptional regulation. This review discusses observations from multiple diseases and models in which tissue-infiltrating T cells produce factors associated with B cell help, including IL-21 and the B cell chemoattractant CXCL13, yet vary dramatically in their resemblance to Tfh cells. Particular attention is given to the PD-1hi CXCR5− Bcl6low T peripheral helper (Tph) cell population in rheumatoid arthritis, which infiltrates inflamed synovium through expression of chemokine receptors such as CCR2 and augments synovial B cell responses via CXCL13 and IL-21. The factors that regulate CD4+ T cell production of CXCL13 and IL-21 in these settings are also discussed. Understanding the range of T cell populations that can provide help to B cells within chronically inflamed tissues is essential to recognize these cells in diverse inflammatory conditions and to optimize either broad or selective therapeutic targeting of B cell-helper T cells.

CD4+T follicular helper (Tfh) cells in human tonsil and blood are clonally convergent, but divergent from non-Tfh CD4+cells

“…In line with previous observations, effector Tfh GC (CXCR5 hi PD-1 hi ) were the major sources of IL-21 and IL-4 and were only present in tonsil (Dan et al, 2019;He et al, 2013;Heit et al, 2017;Locci et al, 2013). The presence of Tfh GC cells in tonsils suggested a probable ongoing immune response in this tissue (Baumjohann et al, 2013;Hansen et al, 2016;Havenar-Daughton et al, 2016), which was not surprising considering that tonsillectomy is often a therapeutic surgical solution for recurrent chronic viral and bacterial infections (Dan et al, 2019;Grivel and Margolis, 2009;Rao, 2018). We also showed that Tfh GC cells are enriched in CXCR3cells and produced little IFN-g (Ma et al, 2009;Ploquin et al, 2011).…”

PD‐1‐expressing MAIT cells from patients with tuberculosis exhibit elevated production of CXCL13

“…CXCL13 is a chemokine that recognizes CXCR5, a featured marker for Tfh cells . CXCL13 appears to be more specific marker for T‐B cell interaction and recruits CXCR5 + B cells and Tfh to lymphoid follicles . The production of IL‐21 by Tfh is important for B cell proliferation and differentiation into plasma cells .…”

“…T cell‐dependent production of antibodies to many different antigens requires T cell help. Follicular helper T cells (Tfh), with high expression of CXCR5, PD‐1 and ICOS, are critical in germinal centre (GC) reaction of B cells and determine the quality of humoral responses . Circulating Tfh (cTfh) cells in blood are also found, which are probably linked developmentally and functionally to GC Tfh .…”

“…32 CXCL13 appears to be more specific marker for T-B cell interaction and recruits CXCR5 + B cells and Tfh to lymphoid follicles. 33 The production of IL-21 by Tfh is important for B cell proliferation and differentiation into plasma cells. 34 Recently, CXCR5 − Tfh-like cells with similar function are reported.…”

Mapping gene regulatory networks of primary CD4+T cells using single-cell genomics and genome engineering

“…Th 17 ) (1-4), signal and recruit B cells (e.g. Th 1 and Th 2 ) (5)(6)(7)(8)(9)(10)(11), and induce tolerance in the tissue microenvironment (e.g. T reg ) (12,13).…”