Multiple treg suppressive modules and their adaptability

Foxp3+ regulatory T cells (Tregs) are a constitutively immunosuppressive cell type critical for the control of autoimmunity and inflammatory pathology. A range of mechanisms of Treg suppression have been identified and it has not always been clear how these different mechanisms interact in order to properly suppress autoimmunity and excessive inflammation. In recent years it has become clear that, while all Tregs seem to share some core suppressive mechanisms, they are also able to adapt to their surroundings in response to a variety of stimuli by homing to the sites of inflammation and exerting ancillary suppressive functions. In this review, we discuss the relevance and possible modes of Treg adaptability and put forward a modular model of Treg suppressive function. Understanding this flexibility may hold the key to understanding the full spectrum of Treg suppressive behavior

Regulatory T Cells Control Antigen-Specific Expansion of Tfh Cell Number and Humoral Immune Responses via the Coreceptor CTLA-4

SummaryCD4+Foxp3-expressing Treg cells, which constitutively express the inhibitory coreceptor CTLA-4, are indispensable for immune homeostasis. We determined the roles of Treg cells and T follicular regulatory (Tfr) cells in the control of humoral immune responses. Depletion of Treg cells, blocking of CTLA-4 or a Treg cell specific reduction in CTLA-4 expression, resulted in an increase in the formation of antigen-specific Tfh cells, germinal center (GC), and plasma and memory B cells after vaccination. In the absence of Treg cell-expressed CTLA-4, large numbers of Tfr cells were present but were unable to restrain Tfh cell and GC formation. Temporary Treg cell depletion during primary immunization was sufficient to enhance secondary immune responses. Treg cells directly inhibited, via CTLA-4, B cell expression of CD80 and CD86, which was essential for Tfh cell formation. Thus, Treg and Tfr cells control Tfh cell and germinal center development, via CTLA-4-dependent regulation of CD80 and CD86 expression

T cell self-reactivity forms a cytokine milieu for spontaneous development of IL-17+ Th cells that cause autoimmune arthritis

This report shows that highly self-reactive T cells produced in mice as a result of genetically altered thymic T cell selection spontaneously differentiate into interleukin (IL)-17–secreting CD4+ helper T (Th) cells (Th17 cells), which mediate an autoimmune arthritis that clinically and immunologically resembles rheumatoid arthritis (RA). The thymus-produced self-reactive T cells, which become activated in the periphery via recognition of major histocompatibility complex/self-peptide complexes, stimulate antigen-presenting cells (APCs) to secrete IL-6. APC-derived IL-6, together with T cell–derived IL-6, drives naive self-reactive T cells to differentiate into arthritogenic Th17 cells. Deficiency of either IL-17 or IL-6 completely inhibits arthritis development, whereas interferon (IFN)-γ deficiency exacerbates it. The generation, differentiation, and persistence of arthritogenic Th17 cells per se are, however, insufficient for producing overt autoimmune arthritis. Yet overt disease is precipitated by further expansion and activation of autoimmune Th17 cells, for example, via IFN-γ deficiency, homeostatic proliferation, or stimulation of innate immunity by microbial products. Thus, a genetically determined T cell self-reactivity forms a cytokine milieu that facilitates preferential differentiation of self-reactive T cells into Th17 cells. Extrinsic or intrinsic stimuli further expand these cells, thereby triggering autoimmune disease. Intervention in these events at cellular and molecular levels is useful to treat and prevent autoimmune disease, in particular RA

Preferential recruitment of CCR6-expressing Th17 cells to inflamed joints via CCL20 in rheumatoid arthritis and its animal model

This report shows that interleukin (IL) 17–producing T helper type 17 (Th17) cells predominantly express CC chemokine receptor (CCR) 6 in an animal model of rheumatoid arthritis (RA). Th17 cells induced in vivo in normal mice via homeostatic proliferation similarly express CCR6, whereas those inducible in vitro by transforming growth factor β and IL-6 additionally need IL-1 and neutralization of interferon (IFN) γ and IL-4 for CCR6 expression. Forced expression of RORγt, a key transcription factor for Th17 cell differentiation, induces not only IL-17 but also CCR6 in naive T cells. Furthermore, Th17 cells produce CCL20, the known ligand for CCR6. Synoviocytes from arthritic joints of mice and humans also produce a large amount of CCL20, with a significant correlation (P = 0.014) between the amounts of IL-17 and CCL20 in RA joints. The CCL20 production by synoviocytes is augmented in vitro by IL-1β, IL-17, or tumor necrosis factor α, and is suppressed by IFN-γ or IL-4. Administration of blocking anti-CCR6 monoclonal antibody substantially inhibits mouse arthritis. Thus, the joint cytokine milieu formed by T cells and synovial cells controls the production of CCL20 and, consequently, the recruitment of CCR6+ arthritogenic Th17 cells to the inflamed joints. These results indicate that CCR6 expression contributes to Th17 cell function in autoimmune disease, especially in autoimmune arthritis such as RA