Foxp3+ Treg cells in humoral immunity

International Immunology, Feb 2014

Treg cells are essential for the maintenance of immune homeostasis and prevention of autoimmunity. In humoral immune responses, loss of Treg cell function causes increased levels of serum autoantibodies, hyper-IgE, spontaneous generation of germinal centres, and enhanced numbers of specialised T follicular helper cells (Tfh cells) controlled by the lineage-defining transcription factor BCL-6 (B-cell lymphoma 6). Recent studies have demonstrated that a subset of Treg cells [T follicular regulatory (Tfreg) cells] are able to co-opt the follicular T-cell program by gaining expression of BCL-6 and travelling to the follicle where they have an important role in the control of expansion of Tfh cells and the germinal centre reaction. However, the mechanisms by which they exert this control are still under investigation. In this review, we discuss the effects of Treg cells on humoral immunity and the mechanisms by which they exert their regulatory function.

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Foxp3+ Treg cells in humoral immunity

Foxp 0 T 0 James B.Wing 0 ShimonSakaguchi 0 0 Department of Experimental Immunology, WPI Immunology Frontier Research Center, Osaka University , Suita 565-0871 International Immunology, Vol. 26, No. 2, pp. 61-69 reg regulatory function. Treg cells are essential for the maintenance of immune homeostasis and prevention of autoimmunity. In humoral immune responses, loss of Treg cell function causes increased levels of serum autoantibodies, hyper-IgE, spontaneous generation of germinal centres, and enhanced numbers of specialised T follicular helper cells (Tfh cells) controlled by the lineage-defining transcription factor BCL-6 (B-cell lymphoma 6). Recent studies have demonstrated that a subset of Treg cells [T follicular regulatory (Tfreg) cells] are able to co-opt the follicular T-cell program by gaining expression of BCL-6 and travelling to the follicle where they have an important role in the control of expansion of Tfh cells and the germinal centre reaction. However, the mechanisms by which they exert this control are still under investigation. In this review, we discuss the effects of Treg cells on humoral immunity and the mechanisms by which they exert their Introduction The generation of high-affinity antibody is critical to protection from infectious disease and other threats. During the T-dependent antibody response, antigen-presenting B cells at the border of the T-cell zone form cognate interactions with Th cells and, following co-stimulatory interactions, may either form short-lived extrafollicular plasmablast cellsresponsible for rapid but low-affinity antibody production (1)or traverse to the B-cell follicle. Once activated in situ there, B cells begin to proliferate and form a germinal centre where longerlasting, high-affinity responses are induced (2,3). Although germinal centres are critical for the generation of protective antibody responses, their dysregulation may lead to autoimmunity (4). A large proportion of B cells are autoreactive at an early stage of development (5) and, despite central tolerance mechanisms such as receptor editing, clonal deletion and anergy (68), autoreactive B cells are still present in the periphery. Additionally, somatic hypermutation within the germinal centre allows the generation of autoreactive B cells during the response to foreign antigens (9) and also allows chromosomal translocations that have a causative role in the generation of lymphomas (1012). As such, it is evident that self-reactive germinal centres must be controlled to avoid autoimmunity but also that some level of regulation of even non-self-reactive germinal centres must be in place. This is achieved by a number of mechanisms such as antibody feedback (13) and follicle-resident CD8+ T cells (14,15). However, in this article we will focus on the contribution of Foxp3-expressing Treg cells to the control of the humoral response. Various phenotypes of T cells have immunosuppressive properties, but the best understood are CD4+CD25+Foxp3+ Treg cells. These cells are critical to the regulation of humoral immunity as both mice and humans with loss of Foxp3 function have raised levels of serum antibodies (16,17). More recently, it has also become clear that regulate the germinal centre response (1820). Treg cells are able to travel into the B-cell follicle and directly Foxp3+ Treg cells make up around 10% of peripheral CD4+ T cells and have a critical role in the maintenance of immune self-tolerance and homeostasis (21,22). The function of Treg cells is controlled by two key features: (i) the expression of the transcription factor Foxp3 (2325), responsible for the maintenance of several key phenotypic factors in Treg-cell function such as CTLA-4 expression and repression of IL-2 production and (ii) the maintenance of Treg-type epigenetics, a specific DNA hypomethylation pattern that is required for the stability and full functional capabilities of Treg cells (26). In cases where expression of Foxp3 is lost, such as in the scurfy mouse strain and immune dysregulation polyendocrinopathy enteropathy X-linked syndrome (IPEX) patients, the resulting loss of Treg-cell function causes a range of severe immune disorders such as widespread autoimmunity, immunopathology and lymphoproliferation In terms of humoral immunity, Foxp3-deficient mice have uncontrolled germinal centre reactions and large numbers of plasma cells and T follicular helper cells (Tfh cells) (20,30). In the K/BxN mouse model of autoantibody-driven arthritis, loss of Treg-cell function, owing to the introduction of the Foxp3 scurfy mutation, leads to accelerated production of pathogenic autoantibodies and accumulation of spleenic plasma cells (30,31). In humans, B cells from IPEX patients produce large amounts of autoreactive antibodies (32). Another characteristic feature of the loss of Foxp3 function is hyper-IgE in both mice (33) and IPEX patients (29). This may be partly because of the disproportionate effect of the loss of Treg-cel (...truncated)


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James B. Wing, Shimon Sakaguchi. Foxp3+ Treg cells in humoral immunity, International Immunology, 2014, pp. 61-69, 26/2, DOI: 10.1093/intimm/dxt060