T Follicular Helper Cells in Autoimmune Disorders

Abstract

T follicular helper (Tfh) cells are a distinct subset of CD4+ T lymphocytes, specialized in B cell help and in regulation of antibody responses. They are required for the generation of germinal center reactions, where selection of high affinity antibody producing B cells and development of memory B cells occur. Owing to the fundamental role of Tfh cells in adaptive immunity, the stringent control of their production and function is critically important, both for the induction of an optimal humoral response against thymus-dependent antigens but also for the prevention of self-reactivity. Indeed, deregulation of Tfh activities can contribute to a pathogenic autoantibody production and can play an important role in the promotion of autoimmune diseases. In the present review, we briefly introduce the molecular factors involved in Tfh cell formation in the context of a normal immune response, as well as markers associated with their identification (transcription factor, surface marker expression, and cytokine production). We then consider in detail the role of Tfh cells in the pathogenesis of a broad range of autoimmune diseases, with a special focus on systemic lupus erythematosus and rheumatoid arthritis, as well as on the other autoimmune/inflammatory disorders. We summarize the observed alterations in Tfh numbers, activation state, and circulating subset distribution during autoimmune and some other inflammatory disorders. In addition, central role of interleukin-21, major cytokine produced by Tfh cells, is discussed, as well as the involvement of follicular regulatory T cells, which share characteristics with both Tfh and regulatory T cells.

Sex differences in Tfh cell help to B cells contribute to sexual dimorphism in severity of rat collagen-induced arthritis

“…Considering that Tfh cells specialized in providing help to B cells are essential for GC formation, affinity maturation, and the development of memory B cells 27 , whereas Tfr cells are critical for controlling Tfh cell:B cell interaction 29,30 , dLN cells were also examined for their frequency. To identify these cells, conventional Foxp3-CD4+ cells and Foxp3+ CD4+ cells encompassing predominantly regulatory T cells 44 (Supplementary Fig.…”

“…Conventional CD4+ T cells differentiate into Tfh cells through a specific pathway that terminates in the high expression of the B-cell follicle homing chemokine (C-X-C motif) receptor 5 (CXCR5) and their localization to the GCs 27,28 . Thus, the stringent control of Tfh cell generation and function is critically important for the induction of an optimal humoral response against thymus-dependent antigens and the prevention of self-reactivity, alike 29,30 . Consistently, deregulations of Tfh response can contribute to the production of pathogenic autoantibodies, and thereby the promotion of autoantibody-mediated autoimmune diseases, including RA 29,30 .…”

“…Thus, the stringent control of Tfh cell generation and function is critically important for the induction of an optimal humoral response against thymus-dependent antigens and the prevention of self-reactivity, alike 29,30 . Consistently, deregulations of Tfh response can contribute to the production of pathogenic autoantibodies, and thereby the promotion of autoantibody-mediated autoimmune diseases, including RA 29,30 . To corroborate this notion, in CIA, T-cell-specific CXCR5 deficiency results in a significant reduction in the formation of GCs leading to the decreased levels of collagen-specific antibodies and the resistance to CIA induction 25 .…”

Di-(2-ethylhexyl)-phthalate interferes with T-follicular helper cell differentiation and cytokine secretion through signaling lymphocytic activation molecule family member-1

“…It has been subsequently shown these cells have an even larger role in host immunocompetence. Specifically, it has been shown that abnormal differentiation and hyperfunction of T fh cells can cause an immune imbalance in a host (Ma and Deenick 2014;Ueno et al 2015;Varricchi et al 2016;Gensous et al 2018).…”

ICOS enhances follicular T helper responses and deteriorates the pathogenic process of liver in mice infected withSchistosoma japonicum

“…Tfh cells can promote antigen-specific B cell activation, germinal center formation and humoral responses [12,13]. In addition, Tfh cells are involved in the pathogenic process of some autoimmune diseases [14-16] and participate in defensing against parasite infection [17,18]. Indeed, increased frequency of Tfh cells is detected in rodent with S. japonicum infection and Tfh cells activated by ICOS + macrophages infiltrate into the liver and enhance the liver injury in mice infected with S. japonicum [19].…”