Interleukin 10 acts on regulatory T cells to maintain expression of the transcription factor Foxp3 and suppressive function in mice with colitis

Abstract

Regulatory T cells (T reg cells) that express the transcription factor Foxp3 suppress the activity of other cells. Here we show that interleukin 10 (IL-10) produced by CD11b + myeloid cells in recombination-activating gene 1-deficient (Rag1 −/− ) recipient mice was needed to prevent the colitis induced by transferred CD4 + CD45RB hi T cells. In Il10 −/− Rag1 −/− mice, T reg cells failed to maintain Foxp3 expression and regulatory activity. The loss of Foxp3 expression occurred only in recipients with colitis, which indicates that the requirement for IL-10 is manifested in the presence of inflammation. IL-10 receptor-deficient (Il10rb −/− ) T reg cells also failed to maintain Foxp3 expression, which suggested that host IL-10 acted directly on the T reg cells. Our data indicate that IL-10 released from myeloid cells acts in a paracrine manner on T reg cells to maintain Foxp3 expression. CD4 + regulatory T cells (T reg cells) express the transcription factor Foxp3 (A002750), which is required for their suppressive function. A T cell-transfer model of colitis has been widely used to study the function of T reg cells in vivo. When CD4 + CD45RB hi T cells are transferred into immunodeficient mice, some of the transferred T cells secrete proinflammatory cytokines and induce an inflammatory bowel disease-like syndrome 1,2 . Cotransfer of sufficient numbers of T reg cells can prevent or even cure this disease 3,4 . The transferred T reg cell populations expand considerably in vivo, and most maintain Foxp3 expression 5,6 .Mice deficient in interleukin 10 (IL-10 (A001243); Il10 −/− mice) or the IL-10 receptor β-chain (IL-10Rβ (A001245); Il10rb −/− mice) develop spontaneous inflammation of the large intestine, a process dominated by a T helper type 1 immune response7 ,8 . Many cell types can produce IL-10, however, and therefore the IL-10 source(s) needed to prevent inflammation must be identified. Much emphasis has been placed on the role of IL-10 released by CD4 + T cells, and in fact mice with conditional deletion of IL-10 in the CD4 + subset develop spontaneous inflammation of the intestine 9 . Mice with deletion of IL-10 solely in Foxp3 + cells also develop inflammation in the intestine and elsewhere, although the pathogenesis is less intense than that in mice completely lacking . Transgenic mice that overexpress IL-10 in intestinal epithelial cells are protected from colitis11, which suggests that IL-10 from nonlymphoid sources can be beneficial, although altered expression in the transgenic mice may not be physiologically relevant. NIH Public AccessTo further elucidate the cellular and molecular basis of the function of IL-10 in regulating colitis, we used the T cell-transfer model described above. We found that IL-10 from nonlymphoid cells, particularly CD11b + CD11c + cells, had an unexpectedly important influence on the development of colitis. Furthermore, we provide evidence that this IL-10 acted in part on T reg cells to maintain their expression of Foxp3, which was otherwise lost in inflammatory condit...

Deficiency of haematopoietic-cell-derived IL-10 does not exacerbate high-fat-diet-induced inflammation or insulin resistance in mice

“…These symptoms were not observed in any of the wild-type BMT mice. These observations are consistent with several previous studies that implicate IL-10 production by lymphoid or myeloid cells in the prevention of inflammation of the large intestine and, ultimately, the development of colitis [48][49][50]. Given that these mice (7/18 Il10-KO BMT mice) displayed a variety of colitis-like symptoms and did not increase their fat mass during the 12 week high-fat-diet period, we excluded these mice from the study.…”

Regulatory T Cell–Derived IL-10 Ameliorates Crescentic GN

“…24 However, there are controversial results since Chaudhry and coworkers did not detect any differences in Foxp3 expression by IL-10R-deficient Foxp3 + Tregs. 25 Moreover, it is postulated that IL-10 released by Tregs acts in an autocrine manner in order to self-regulate and expand Tregs themselves.…”

“…25 Moreover, it is postulated that IL-10 released by Tregs acts in an autocrine manner in order to self-regulate and expand Tregs themselves. 18,23,24,26 Therefore, to exclude any influence of IL-10 deficiency with respect to Foxp3 stability, we determined the number of Foxp3 + Tregs in the inflamed kidney by immunohistochemistry. Of note, the numbers of renal Tregs were similar both in nephritic intact expression of Foxp3 in Tregs lacking IL-10.…”

FOXP3+ regulatory T cells and their functional regulation

“…27 Former FOXP3 1 T cells (exFOXP3 1 T cells), were also found particularly increased in inflamed gut-associated tissues. [27][28][29] Bluestone and colleagues performed a fate mapping study with Foxp3-GFP-Cre BAC transgenic mice to trace the stability of FOXP3 1 T cells and found that 10%-20% of FOXP3 1 Treg cells lose FOXP3 expression and exhibit inflammatory Th cell phenotypes with the ability to secrete IFN-c and IL-17. 30 On the molecular level, we have identified how the stress-activated Stub1-Hsp70 complex plays a critical role in the degradation of FOXP3 and promotion of Treg cell conversion into Th1-like cells.…”