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

Abstract

In the present study, we show that human self-MHC-reactive (autoreactive) T cell clones are functionally distinct from Ag-specific T cell clones. Self-MHC-reactive T cells exhibited helper function for B cell Ig production when cultured with non-T cells alone, and they exhibit suppressor function when cultured with PWM- or rCD40 ligand (rCD40L)-activated non-T cells, whereas tetanus toxoid (TT)-specific clones exhibited only helper function in the presence of TT with or without PWM or rCD40L. Addition of neutralizing Abs to the cultures showed that the suppression was mediated by TGF-β but not by IL-10 or IFN-γ. The self-MHC-reactive clones also inhibited proliferation of primary CD4+ T cells and TT-specific T cell clones, but in this case the inhibition was mediated by both IL-10 and TGF-β. In further studies, the interactions between self-MHC-reactive T cell clones and non-T cells that led to suppressor cytokine production have been explored. We found that prestimulation of non-T cells for 8 h with PWM or for 48 h for rCD40L results in non-T cells capable of inducing self-MHC-reactive T cell to produce high levels of TGF-β and IL-10. In addition, these prestimulation times coincided with peak induction of HLA-DR and costimulatory B7 molecule (especially CD86) expression on B cells. Finally, addition of CTLA-4/Fc or blocking F(ab′)2 anti-CTLA-4 mAb, plus optimally stimulated non-T cells, to cultures of self-MHC-reactive clones inhibited the induction of TGF-β but not IL-10 or IFN-γ production. In summary, these studies show that activated self-MHC-reactive T cells have the cytokine phenotype of Th3 or T regulatory cell 1 and thus may be important regulatory cells that mediate oral and peripheral tolerance and prevent the development of autoimmunity.

Induction of Autoantibody Production Is Limited in Nonautoimmune Mice

“…2B and 4C). Analogous findings have been reported in other models (33)(34)(35). For instance, the same self-MHC-reactive T cells helped as well as suppressed B cell Ig production under different conditions (33).…”

B cells alter the phenotype and function of follicular‐homing CXCR5+ T cells

“…Together, these observations suggest that the ability of ICOS to support IL-10 production by T cells plays a critical role in the provision of help to B cells. Furthermore, our results raise the possibility of two distinct types of IL-10-secreting memory T cells in humans: Tr1 cells that inhibit T and B cell functions, lack IL-2 production and do not depend on ICOS for IL-10 secretion [33,34], and the subset of B helper T cells described here that readily produces IL-2 and requires ICOS signaling for production of IL-10.…”

“…In contrast, few clones were clearly positive for IL-4, although interestingly, all T cell clones secreted moderate levels of TGF-b. Previously, IL-10 production has been primarily associated with T regulatory type 1 (Tr1) cells that are known to suppress the function of both T and B cells via production of IL-10 and TGF-b, respectively [33,34]. These cells are additionally characterized by limited IL-2 production and reduced proliferative capacity in vitro.…”

Impaired regulatory T cell function in germ‐free mice

“…Other subsets of Treg are induced in the periphery and are referred to as Th3 [12][13][14] and Tr1 cells [15][16][17][18][19] can also generate Treg. This implies that the state of the APC and the local cytokine milieu, e.g.…”

“…Lack of a functional Foxp3 gene result in the severe autoimmune syndrome IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome), characterized by organ-specific autoimmunity, colitis and high IgE levels [10,11]. Mice with spontaneous or induced mutations in the Foxp3 gene that impair Foxp3 expression fail to develop CD4 + CD25 + Treg and exhibit a syndrome similar to IPEX [5,6].Other subsets of Treg are induced in the periphery and are referred to as Th3 [12][13][14] and Tr1 cells [15][16][17][18][19] can also generate Treg. This implies that the state of the APC and the local cytokine milieu, e.g.…”