Control of the Germinal Center by Follicular Regulatory T Cells During Infection

Abstract

Follicular regulatory T cells (Tfr) are a unique subset of CD4 T cells that control and impact adaptive immune responses in the lymphoid follicles and germinal centers (GC). Since their relatively recent discovery, several studies have revealed that Tfr interact with other cells within this niche and shape ensuing responses. Recent advances defining the functional and developmental characteristics of Tfr have revealed key characteristics of Tfr differentiation, GC recruitment and retention, and regulatory properties. Further, Tfr shape the GC response and balance tolerance through interactions with Tfh, by modifying Tfh number, diversity and function, as well as with B cells. Mechanisms by which Tfr regulate the GC include cell-to-cell interactions with Tfh and B cells, as well as altering their environment through cytokine production and sequestration. Tfr have been shown to have a diverse T cell receptor (TCR) repertoire and can be specific for immunizing agents, demonstrating a potential role in vaccine development. Due to these important characteristics and functions, Tfr play a major role in immune tolerance, response to infection, and vaccine efficacy.

Ethanol consumption inhibits TFH cell responses and the development of autoimmune arthritis

“…Hence, inhibition of IL-21 may be better suited in preventing the transition from autoimmunity to inflammation rather than inhibiting the effector phase of the disease. Moreover, it has been shown that defective T FH cell function caused by a reduction in PD-1 resulted in decreased T-cell dependent antibody responses independent of IL-21 67 . Our study also showed that PD-1 levels are consistently down-regulated on T FH cells following EtOH treatment, suggesting that alcohol-feeding resembles a more complex physiology extending beyond the effects of IL-21, presumably also preventing functional T FH :B cell interaction.…”

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

“…This was in line with previous data indicating that the ratio between production levels of cytokines driving IgG subclass switching rather than their absolute concentrations determines IgG subclass profile 50 . Additionally, given that Tfr cells acting on GC B cells either directly or indirectly, via Tfh-mediated mechanism, influence IgG switching 77 , it may be speculated that sex differences in Tfr-cell regulatory action also contributed to the sex bias in IgG subclass profile. The relationship between the serum levels of different CII-specific IgG subclasses and clinical CIA is not well-defined.…”

Regulatory T cells and co‐evolution of allele‐specific MHC recognition by the TCR

“…In the periphery, antigen stimulation and innate immune inflammatory responses can induce conventional CD4+ T cells to become peripheral CD4+CD25+ FoxP3+ pTregs and more importantly it is now clear that induced pTregs play important roles in both Germinal Centre formation and the regulation of such sites of B lymphocyte hypermutation, memory formation and affinity/avidity maturation . Of more importance for our argument, here is the accumulating evidence for a key role of induced peripheral CD8+ Tregs in the Germinal Centre reaction itself …”

“…[42][43][44][45] Of more importance for our argument, here is the accumulating evidence for a key role of induced peripheral CD8+ Tregs in the Germinal Centre reaction itself. 46,47 All the indications are that the Germinal Centremediated programme of RAG-assisted 'Receptor Mutation, Replacement, Revision' as summed up by Nemazee and Weigert 30 is not restricted to B cells. Thus, RAG-assisted V replacement programmes, particularly the Ig VH segment to Ig VDH replacement process 31,48-50 and secondary V[D]J rearrangements can also be orchestrated in T cells in Germinal Centres or the immediate cellular environment.…”

“…27,55,56 In HIV-1 and similar SIV infections in humans and non-human primates CD8+ Tregs are prominent in Germinal Centres. 46,47 Such follicular CD8+ T cells are also the cells hypermutating in the white pulps of the Germinal Centres of HIV-1 patients analysed by Cheynier et al 6 It is plausible then to suggest that GC-derived CD8+ pTregs are the cellular sites of TCR-SHM in Germinal Centres. In other work, CD4+ T cells have also been reported to express AID deaminase.…”