Tolerance in the Mucosal Immune System

The immune system requires a mechanism for generating antigen specific tolerance to maintain immune homeostasis and control the harmful effects of auto-antigen reactive T lymphocytes. Several mechanisms have been proposed to allow the immune system to suppress the activity of certain T cell clones including clonal deletion, the induction of anergy and antigen specific suppression (reviewed in ref. 23). Recent experiments both in vitro and in animal models of autoimmune disease have characterised different populations of regulatory T lymphocytes that suppress antigen specific lymphocyte responses by the release of cytokines and also by cell:cell interactions.

Groux et al have demonstrated that in vitro repetitive antigenic stimulation of human and murine T cells in the presence of IL-10 leads to the formation of a subset of regulatory T cells termed T regulatory 1 (Tr1) cells.24 These cells have low proliferative capacity and secrete high levels of IL-10, no IL-4 and low levels of IL-2. They are immune suppressive in vitro and will inhibit the antigen-induced proliferative response of naïve elutriated T cells in a contact independent manner. More importantly, Tr1 cells can be shown to be immunosuppressive in vivo. Transfer ofTr1 clones derived from CD4+ T cells expressing a transgenic T cell receptor specific for ovalbumin are able to suppress the CD45RBhigh CD4+ T cells induced colitis in SCID mice. This effect is dependent on the in vivo activation of the Tr1 clones, as they only inhibit colitis in recipients receiving ovalbumin in their drinking water initia tion of this regulation is antigen specific, the effector response is not, as the Tr1 clones are able to suppress the function ofT cells responding to many differing intestinal antigens (a phenomenon termed antigen-driven bystander suppression).

Powrie et al have suggested that these Tr1 clones are the 'in vitro' equivalent of the regulatory cells that mediate the protective functions of the CD45RBlow subset of CD4+ T cells in the transfer model of colitis.25 Further characterisation of the regulatory subset of CD45RBlow CD4+ cells in this model has demonstrated that they express the IL-2 receptor a-chain (CD25) and comprise 5-10% of circulating CD4+ cells.25 This finding is supported by reports that the elimination of the CD4+CD25+ cells leads to a variety of autoimmune conditions in genetically susceptible mice.26 It is not clear whether these cells mediate their effects via cytokine release or cell:cell contact, although several experiments have demonstrated that the release of IL-10 and TGF-P is important.2427

The ability of regulatory T cells to inhibit inflammatory responses may involve impairment of antigen presentation by dendritic cells via a reduction in costimulatory molecule expression. Alternatively regulatory T cells may interrupt the proliferative capacity of activated T cells, preventing their accumulation within the intestine. Finally, the release of immunoregulatory cytokines (such as IL-10 and TGF-P) by regulatory T cells may reduce the release of pro-inflammatory cytokines and chemokines by activated macrophages.

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