There is now compelling evidence that CD4+ T cells, specialized in suppressing immune responses, play a critical role in immune regulation. Three major populations of T regulatory (Treg) cells have been identified based on their distinct phenotype (CD4+CD25+) or cytokine secretion patterns (Tr1 and Th3 cells). While the CD4+CD25+ subset mediates suppression in a non-Ag-specific manner, the later Tr cell types may act in an Ag-specific way. Tr1 cells can be distinguished from Th3 cells because the former preferentially exert their regulatory effects via production of IL-10 (Roncarolo et al., 2001), while Th3 cells preferentially secrete the immunosuppressive cytokine TGF-p. Tr1 cells exist naturally in the human mucosa and maintain intestinal homeostasis against bacterial pathogens (Khoo et al., 1997) and parasites (Satoguina et al., 2002) via the production of IL-10 and TGF-p. Similarly, MHC-autoreactive Tr1-like TCCs isolated from the peripheral blood of healthy donors suppressed antigen-specific T cell responses by the secreting IL-10 and TGF-P (Kitani et al., 2000).
In a recent study, we assessed whether the presence or absence of Dsg3-specific Tr1 cells in Dsg3-responsive healthy donors and PV patients, respectively, may account for the development of tolerance versus autoimmunity against Dsg3. In fact, Dsg3-reactive IL-10-secreting Tr1 cells were identified in 80% of healthy carriers of PV-associated HLA class II alleles and in only 17% of PV patients whose cells suppressed the proliferative response of Dsg3-reactive Th cells. The Dsg3-specific Tr1 cells secreted IL-10, TGF-P, and IL-5 upon Ag stimulation, proliferated in response to IL-2, but not to Dsg3 or mitogenic stimuli, and inhibited the proliferative response of Dsg3- and TT-responsive Th clones in both Ag-specific (Dsg3) and cell number-dependent manners. Moreover, their inhibitory effect was blocked by Ab against IL-10, TGF-P, and by paraformaldehyde fixation. These observations strongly suggest that (a) Dsg3-responsive Tr1 cells predominate in healthy individuals, (b) their growth requires the presence of IL-2, and (c) they exert Dsg3-dependent inhibitory function by the secretion of IL-10 and TGF-P. These findings suggest that Dsg3-specific Tr may be involved in the maintenance of peripheral tolerance to Dsg3 in healthy individuals and in the restoration of tolerance against Dsg3 in PV patients.
There is evidence that Tr1 cells may indeed act in an Ag-specific manner. In nickel (Ni) allergy, nonallergic subjects carry Ni-specific T cells that fulfill the criteria of Tr1 cells based on their cytokine profile (higher IL-10, IL-5, IFN-y, and low IL-4 levels) and their ability to suppress the proliferative response of Ni-activated Th1 cells (Cavani et al., 2000) and may thus be critically involved in the downreg-ulation of Ni-specific Th cell responses in vivo. IL-10+ Tr cells also were detected in patients allergic to bee venom upon specific immunotherapy with phospholi-pase A, which suppressed the proliferative response of allergen-specific Th cells (Akdis et al., 1998). Moreover, the expression of IL-10 increased during specific immunotherapy with phospholipase A, suggesting that the protective effect of this regimen was directly correlated to the presence of IL-10+ allergen-specific Tr cells.
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