Transforming Growth Factor β (TGF-β)-dependent Inhibition of T Helper Cell 2 (Th2)-induced Autoimmunity by Self–Major Histocompatibility Complex (MHC) Class II–specific, Regulatory CD4+ T Cell Lines

Abstract

Autoreactive anti–MHC class II T cells are found in Brown Norway (BN) and Lewis (LEW) rats that receive either HgCl2 or gold salts. These T cells have a T helper cell 2 (Th2) phenotype in the former strain and are responsible for Th2-mediated autoimmunity. In contrast, T cells that expand in LEW rats produce IL-2 and prevent experimental autoimmune encephalomyelitis, a cell-mediated autoimmune disease. The aim of this work was to investigate, using T cell lines derived from HgCl2-injected LEW rats (LEWHg), the effect of these autoreactive T cells on the development of Th2-mediated autoimmunity. The five LEWHg T cell lines obtained protect against Th2-mediated autoimmunity induced by HgCl2 in (LEW × BN)F1 hybrids. The lines produce, in addition to IL-2, IFN-γ and TGF-β, and the protective effect is TGF-β dependent since protection is abrogated by anti-TGF-β treatment. These results identify regulatory, TGF-β–producing, autoreactive T cells that are distinct from classical Th1 or Th2 and inhibit both Th1- and Th2-mediated autoimmune diseases.

Activated Self-MHC-Reactive T Cells Have the Cytokine Phenotype of Th3/T Regulatory Cell 1 T Cells

“…Finally, it has been shown that T cell clones developed in the presence of IL-10, now termed Tr1 cells, produce IL-10 and/or TGF-␤ and prevent colonic inflammation in SCID mice reconstituted with naive CD4 ϩ T cells that otherwise induce colitis (17). Taken together, these studies draw attention to the possibility that counterregulatory cells controlling autoimmunity (15,16,39,44) or inflammation of the gastrointestinal tract are actually self-MHC-reactive T cells. However, further work will be necessary to substantiate this possibility, including the isolation of regulatory cells occurring during (after) the induction of autoimmune inflammation of the specificity of such cells.…”

“…In contrast, treatment of Lewis rats with HgCl 2 also elicited SR T cells, but in this case the T cells prevented rather than caused autoimmune disease when administered to rats undergoing induction of experimental autoimmune encephalitis or HgCl 2 -induced autoimmunity (40). Although the autoreactive T cells mediating disease in the HgCl 2 autoimmunty model produced Th2 cytokines, the autoreactive T cells preventing disease produce IFN-␥ and high levels of TGF-␤, and it is the latter cytokine that was responsible for disease prevention because the administration of anti-TGF-␤ along with the autoreactive cells abrogated prevention (16). These and similar studies in animal models of diabetes establish that self-MHC-reactive T cells producing TGF-␤ can act as counterregulatory cells in autoimmune states (15).…”

“…The possible relation of self-MHC-reactive T cells producing suppressor cytokines to autoimmune disease has recently been explored in several animal models of autoimmunity (15,16,40). In one such model in which Th2 T cell-mediated autoimmunity is elicited in Brown Norway rats by administration of HgCl 2 , the T cells inducing disease have been shown to be reactive to self-MHC class II molecules and/or a self-peptide presented by the latter.…”

“…Such T cells have a unique cytokine production profile in that they produce high levels of TGF-␤ without necessarily producing either Th1 or Th2 cytokines; therefore, they have been dubbed Th3 T cells (12). Th3 cells producing TGF-␤ have also been shown to occur in experimental models of colitis or diabetes or in HgCl 2 -induced autoimmune disease, and in these instances it is thought that such T cells play an important role in disease prevention or cure (13)(14)(15)(16). Recently, another type of regulatory T cell has been identified (in both mice and humans) that may be related to the aforementioned Th3 T cell.…”

Non‐Th2 Regulatory T‐Cell Control of Th1 Autoimmunity

“…Other data (reviewed in [53]) indicated that TGF-b-producing regulatory cells named Th3 cells depended on IL-4 for growth but did not always produce this cytokine even if they finally induced a Th2 switch with subsequent Th1 cell downregulation. The problem was complicated by the observation that some Th3 cells could also inhibit Th2 cells, as demonstrated in a HgCl 2 -induced autoimmune model [54]. It also remains to be understood if there is any relationship between these antigen-induced Th3 cells and the TGF-b-dependent regulatory cells described by Mason in the rat [55] and by Powrie in the mouse [56].…”