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The Wiskott-Aldrich syndrome protein is required for the function of CD4(+)CD25(+)Foxp3(+) regulatory T cells.

Maillard MH, Cotta-de-Almeida V, Takeshima F, Nguyen DD, Michetti P, Nagler C, Bhan AK, Snapper SB - J. Exp. Med. (2007)

Bottom Line: Preincubation of WKO nTreg cells with exogenous interleukin (IL)-2, combined with antigen receptor-mediated activation, substantially rescues the suppression defects.WKO nTreg cells are also defective in the secretion of the immunomodulatory cytokine IL-10.Overall, our data reveal a critical role for WASP in nTreg cell function and implicate nTreg cell dysfunction in the autoimmunity associated with WASP deficiency.

View Article: PubMed Central - PubMed

Affiliation: Gastrointestinal Unit, Massachusetts General Hospital, Boston, MA 02114, USA.

ABSTRACT
The Wiskott-Aldrich syndrome, a primary human immunodeficiency, results from defective expression of the hematopoietic-specific cytoskeletal regulator Wiskott-Aldrich syndrome protein (WASP). Because CD4(+)CD25(+)Foxp3(+) naturally occurring regulatory T (nTreg) cells control autoimmunity, we asked whether colitis in WASP knockout (WKO) mice is associated with aberrant development/function of nTreg cells. We show that WKO mice have decreased numbers of CD4(+)CD25(+)Foxp3(+) nTreg cells in both the thymus and peripheral lymphoid organs. Moreover, we demonstrate that WKO nTreg cells are markedly defective in both their ability to ameliorate the colitis induced by the transfer of CD45RB(hi) T cells and in functional suppression assays in vitro. Compared with wild-type (WT) nTreg cells, WKO nTreg cells show significantly impaired homing to both mucosal (mesenteric) and peripheral sites upon adoptive transfer into WT recipient mice. Suppression defects may be independent of antigen receptor-mediated actin rearrangement because both WT and WKO nTreg cells remodeled their actin cytoskeleton inefficiently upon T cell receptor stimulation. Preincubation of WKO nTreg cells with exogenous interleukin (IL)-2, combined with antigen receptor-mediated activation, substantially rescues the suppression defects. WKO nTreg cells are also defective in the secretion of the immunomodulatory cytokine IL-10. Overall, our data reveal a critical role for WASP in nTreg cell function and implicate nTreg cell dysfunction in the autoimmunity associated with WASP deficiency.

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Proposed model for nTreg cell dysfunction and colitis development in WKO mice. Decreased nTreg cell numbers in both the thymus and the periphery (lymph nodes) are observed in WKO mice and may result from IL-2 deficiency and TCR activation defects. IL-2 deficiency, aberrant nTreg cell homing, activation, and reduced IL-10 secretion lead to impaired suppression of colitogenic T cells and colitis.
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fig7: Proposed model for nTreg cell dysfunction and colitis development in WKO mice. Decreased nTreg cell numbers in both the thymus and the periphery (lymph nodes) are observed in WKO mice and may result from IL-2 deficiency and TCR activation defects. IL-2 deficiency, aberrant nTreg cell homing, activation, and reduced IL-10 secretion lead to impaired suppression of colitogenic T cells and colitis.

Mentions: Although WASP is not required for the development of CD4+ T cells (6, 7), the generation/homeostasis of CD4+CD25+Foxp3+ T cells may be particularly sensitive to WASP deficiency. Numerous studies have demonstrated a critical role for WASP in antigen receptor–induced signaling in T cells (6, 7, 42). Studies using TCR-transgenic mice suggest that WT nTreg cells are generated after recognition of self-antigens in the thymus, with nTreg cell–selective events requiring relatively high affinity interactions (43, 44). CD28 costimulation and IL-2 are also required for efficient nTreg cell generation in thymocytes, as illustrated by decreased nTreg cell numbers in CD28 knockout and IL-2 knockout mice (33, 45, 46). However IL-2 appears to have a more critical role in nTreg cell maintenance in the periphery (33). Although CD28-mediated signals have been shown to partly rescue the proliferation defects of WKO T cells (4, 6), and potential defects in CD28 costimulation in WKO nTreg cells were not assessed in this report, a complementary report suggests that CD28 signaling does not rescue the defects in proliferation by WKO nTreg cells (see Marangoni et al. on p. 369 of this issue). Defects in IL-2 production and secretion have been observed consistently in WKO T cells (2, 6, 7, 42). Exogenous IL-2 can rescue, at least in part, antigen receptor–induced signaling events in both naive WKO T cells (6, 7) and WKO nTreg cells. We have also demonstrated a reduction in CD25 (i.e., IL-2Rα) surface expression on WKO nTreg cells. Collectively, we hypothesize that defective IL-2 production and antigen receptor activation contribute to the observed decrease in numbers and function of naturally occurring nTreg cells in WKO mice (Fig. 7). This defect in antigen receptor activation may result, in part, by an increase in the activation threshold of WKO nTreg cells that is overcome by IL-2 stimulation. This is further supported by recent complementary data directly demonstrating that proliferative defects of WKO nTreg cells can be diminished with increased stimulation through the TCR (Marangoni et al., in this issue). Defective IL-2 secretion or IL-2–induced signaling events are unlikely to be solely responsible for the nTreg cell dysfunction because CD4+Foxp3+ cells from IL-2 or CD25 knockout mice are as suppressive in vitro as WT cells (33). Because Foxp3 is expressed normally in WKO CD4+CD25+ cells, our data do not support a direct role for either WASP or antigen receptor–mediated signaling events in regulating Foxp3 expression and suggest that the suppressive defects in WKO nTreg cells are downstream and/or independent of Foxp3.


The Wiskott-Aldrich syndrome protein is required for the function of CD4(+)CD25(+)Foxp3(+) regulatory T cells.

Maillard MH, Cotta-de-Almeida V, Takeshima F, Nguyen DD, Michetti P, Nagler C, Bhan AK, Snapper SB - J. Exp. Med. (2007)

Proposed model for nTreg cell dysfunction and colitis development in WKO mice. Decreased nTreg cell numbers in both the thymus and the periphery (lymph nodes) are observed in WKO mice and may result from IL-2 deficiency and TCR activation defects. IL-2 deficiency, aberrant nTreg cell homing, activation, and reduced IL-10 secretion lead to impaired suppression of colitogenic T cells and colitis.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2118715&req=5

fig7: Proposed model for nTreg cell dysfunction and colitis development in WKO mice. Decreased nTreg cell numbers in both the thymus and the periphery (lymph nodes) are observed in WKO mice and may result from IL-2 deficiency and TCR activation defects. IL-2 deficiency, aberrant nTreg cell homing, activation, and reduced IL-10 secretion lead to impaired suppression of colitogenic T cells and colitis.
Mentions: Although WASP is not required for the development of CD4+ T cells (6, 7), the generation/homeostasis of CD4+CD25+Foxp3+ T cells may be particularly sensitive to WASP deficiency. Numerous studies have demonstrated a critical role for WASP in antigen receptor–induced signaling in T cells (6, 7, 42). Studies using TCR-transgenic mice suggest that WT nTreg cells are generated after recognition of self-antigens in the thymus, with nTreg cell–selective events requiring relatively high affinity interactions (43, 44). CD28 costimulation and IL-2 are also required for efficient nTreg cell generation in thymocytes, as illustrated by decreased nTreg cell numbers in CD28 knockout and IL-2 knockout mice (33, 45, 46). However IL-2 appears to have a more critical role in nTreg cell maintenance in the periphery (33). Although CD28-mediated signals have been shown to partly rescue the proliferation defects of WKO T cells (4, 6), and potential defects in CD28 costimulation in WKO nTreg cells were not assessed in this report, a complementary report suggests that CD28 signaling does not rescue the defects in proliferation by WKO nTreg cells (see Marangoni et al. on p. 369 of this issue). Defects in IL-2 production and secretion have been observed consistently in WKO T cells (2, 6, 7, 42). Exogenous IL-2 can rescue, at least in part, antigen receptor–induced signaling events in both naive WKO T cells (6, 7) and WKO nTreg cells. We have also demonstrated a reduction in CD25 (i.e., IL-2Rα) surface expression on WKO nTreg cells. Collectively, we hypothesize that defective IL-2 production and antigen receptor activation contribute to the observed decrease in numbers and function of naturally occurring nTreg cells in WKO mice (Fig. 7). This defect in antigen receptor activation may result, in part, by an increase in the activation threshold of WKO nTreg cells that is overcome by IL-2 stimulation. This is further supported by recent complementary data directly demonstrating that proliferative defects of WKO nTreg cells can be diminished with increased stimulation through the TCR (Marangoni et al., in this issue). Defective IL-2 secretion or IL-2–induced signaling events are unlikely to be solely responsible for the nTreg cell dysfunction because CD4+Foxp3+ cells from IL-2 or CD25 knockout mice are as suppressive in vitro as WT cells (33). Because Foxp3 is expressed normally in WKO CD4+CD25+ cells, our data do not support a direct role for either WASP or antigen receptor–mediated signaling events in regulating Foxp3 expression and suggest that the suppressive defects in WKO nTreg cells are downstream and/or independent of Foxp3.

Bottom Line: Preincubation of WKO nTreg cells with exogenous interleukin (IL)-2, combined with antigen receptor-mediated activation, substantially rescues the suppression defects.WKO nTreg cells are also defective in the secretion of the immunomodulatory cytokine IL-10.Overall, our data reveal a critical role for WASP in nTreg cell function and implicate nTreg cell dysfunction in the autoimmunity associated with WASP deficiency.

View Article: PubMed Central - PubMed

Affiliation: Gastrointestinal Unit, Massachusetts General Hospital, Boston, MA 02114, USA.

ABSTRACT
The Wiskott-Aldrich syndrome, a primary human immunodeficiency, results from defective expression of the hematopoietic-specific cytoskeletal regulator Wiskott-Aldrich syndrome protein (WASP). Because CD4(+)CD25(+)Foxp3(+) naturally occurring regulatory T (nTreg) cells control autoimmunity, we asked whether colitis in WASP knockout (WKO) mice is associated with aberrant development/function of nTreg cells. We show that WKO mice have decreased numbers of CD4(+)CD25(+)Foxp3(+) nTreg cells in both the thymus and peripheral lymphoid organs. Moreover, we demonstrate that WKO nTreg cells are markedly defective in both their ability to ameliorate the colitis induced by the transfer of CD45RB(hi) T cells and in functional suppression assays in vitro. Compared with wild-type (WT) nTreg cells, WKO nTreg cells show significantly impaired homing to both mucosal (mesenteric) and peripheral sites upon adoptive transfer into WT recipient mice. Suppression defects may be independent of antigen receptor-mediated actin rearrangement because both WT and WKO nTreg cells remodeled their actin cytoskeleton inefficiently upon T cell receptor stimulation. Preincubation of WKO nTreg cells with exogenous interleukin (IL)-2, combined with antigen receptor-mediated activation, substantially rescues the suppression defects. WKO nTreg cells are also defective in the secretion of the immunomodulatory cytokine IL-10. Overall, our data reveal a critical role for WASP in nTreg cell function and implicate nTreg cell dysfunction in the autoimmunity associated with WASP deficiency.

Show MeSH
Related in: MedlinePlus