Tolerance due to regulatory lymphocytes is distinguished from other forms of self-tolerance by the fact that Treg cells have the potential to suppress self-reactive lymphocytes that recognize antigens different from those recognized by the Treg cell (Fig. 15.9). This type of tolerance is known as regulatory tolerance. The key feature of regulatory tolerance is that regulatory cells can suppress autoreactive lymphocytes that recognize a variety of different self antigens, as long as the antigens are from the same tissue or are presented by the same antigen-presenting cell. As discussed in Chapter 9, two general types of regulatory T cells have been defined experimentally. ‘Natural’ Treg (nTreg) cells are programmed in the thymus to express the transcription factor FoxP3 in response to self antigens. When activated by the same antigens in peripheral tissues, nTreg cells inhibit other self-reactive T cells that recognize antigens in the same tissue to prevent their differentiation into effector T cells or prevent their effector function. ‘Induced’ T (iT ) cells also express FoxP3 but develop in peripheral immune tissues in response to antigens recognized in the presence of TGF-β but in the absence of pro-inflammatory cytokines. Giving animals large amounts of self antigen orally, which induces so-called oral tolerance (see Section 12-18), can sometimes lead to unresponsiveness to these antigens when given by other routes, and can prevent autoimmune disease. Oral tolerance is routinely generated to antigens such as food antigens and is accompanied by the generation of iTreg cells in the gut-draining mesenteric lymph nodes. These cells are known to suppress immune responses to the given antigen in the gut itself, but how the suppression in the rest of the peripheral immune system is achieved is unclear. Many investigators have hypothesized that iTreg cells could have therapeutic potential for the treatment of autoimmune disease if they could be isolated or induced to differentiate and then be infused into patients.
The importance of FoxP3—and the Treg cells whose development and function it controls—in the maintenance of immune tolerance is evident from the fact that humans and mice that carry mutations in the gene for FoxP3 rapidly develop severe, systemic autoimmunity (discussed in Section 15-21). A protective role for FoxP3-expressing Treg cells has been demonstrated in several autoimmune syndromes in mice, including diabetes, EAE, SLE, and inflammation of the large intestine, or colon (colitis). Experiments in mouse models of these diseases have established that FoxP3+ Treg cells actively suppress disease in the normal immune system, as depletion of these cells results in multi-organ autoimmune disease. Treg cells have also been shown to prevent or ameliorate other immunopathologic syndromes, such as graft-versus-host disease and graft rejection, which are described later in this chapter.
The importance of regulatory T cells has been demonstrated in several human autoimmune diseases. For example, in some patients with multiple sclerosis or with autoimmune polyglandular syndrome type 2 (a rare syndrome in which two or more autoimmune diseases occur simultaneously), the suppressive activity of FoxP3+ Treg cells is defective, although their numbers are normal. Thus, Treg cells have an important role in preventing autoimmunity, and a variety of functional defects in these cells may lead to autoimmunity.
FoxP3-expressing Treg cells are not the only type of regulatory lymphocyte that has been identified. For example, FoxP3-negative regulatory T cells characterized by their production of IL-10 are enriched in the intestinal tissues, where they may suppress inflammatory bowel disease (IBD) through an IL-10dependent mechanism. The developmental origins of these cells are not currently understood.