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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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Defective homing of WKO nTreg cells to peripheral lymphoid organs. (A) Reduced accumulation of WKO nTreg cells in the CD45RB transfer model. SCID mice were cotransferred with WT CD4+CD45RBhi and either WT (left) or WKO (right) nTreg cells. 10 wk after transfer, spleen, mesenteric lymph node, and colonic lamina propria cells were collected and stained for CD4 and Foxp3. Shown are representative dot plots of 6 and 10 mice per group. (B) nTreg cells or CD4+CD25− cells were isolated from peripheral lymphoid organs of WT and WKO mice, labeled with CFSE (WT) or TRITC (WKO), and mixed at a 1:1 ratio before intravenous injection to WT mice. Spleen and peripheral and mesenteric lymph nodes of recipient mice were harvested after 12–15 h, and the percentage of WKO lymphocyte homing relative to WT was determined. Shown are averages ± SD of combined data from two experiments including eight (CD4+CD25−) and seven (nTreg cells) mice per group. Dashed line represents the input percentage.
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fig3: Defective homing of WKO nTreg cells to peripheral lymphoid organs. (A) Reduced accumulation of WKO nTreg cells in the CD45RB transfer model. SCID mice were cotransferred with WT CD4+CD45RBhi and either WT (left) or WKO (right) nTreg cells. 10 wk after transfer, spleen, mesenteric lymph node, and colonic lamina propria cells were collected and stained for CD4 and Foxp3. Shown are representative dot plots of 6 and 10 mice per group. (B) nTreg cells or CD4+CD25− cells were isolated from peripheral lymphoid organs of WT and WKO mice, labeled with CFSE (WT) or TRITC (WKO), and mixed at a 1:1 ratio before intravenous injection to WT mice. Spleen and peripheral and mesenteric lymph nodes of recipient mice were harvested after 12–15 h, and the percentage of WKO lymphocyte homing relative to WT was determined. Shown are averages ± SD of combined data from two experiments including eight (CD4+CD25−) and seven (nTreg cells) mice per group. Dashed line represents the input percentage.

Mentions: We have previously demonstrated in vitro and in vivo that WKO mice have global defects in directed leukocyte migration (28). We hypothesized that the failure of WKO nTreg cells to suppress colitis in the CD45RB transfer model may result, at least in part, from defects in migration of WKO nTreg cells to target organs. Consistent with this hypothesis, the numbers of WKO nTreg cells recovered from the spleen, mesenteric lymph nodes, and lamina propria was reduced compared with WT nTreg cells in mice cotransferred with WT CD45RBhi T cells (Fig. 3 A).


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)

Defective homing of WKO nTreg cells to peripheral lymphoid organs. (A) Reduced accumulation of WKO nTreg cells in the CD45RB transfer model. SCID mice were cotransferred with WT CD4+CD45RBhi and either WT (left) or WKO (right) nTreg cells. 10 wk after transfer, spleen, mesenteric lymph node, and colonic lamina propria cells were collected and stained for CD4 and Foxp3. Shown are representative dot plots of 6 and 10 mice per group. (B) nTreg cells or CD4+CD25− cells were isolated from peripheral lymphoid organs of WT and WKO mice, labeled with CFSE (WT) or TRITC (WKO), and mixed at a 1:1 ratio before intravenous injection to WT mice. Spleen and peripheral and mesenteric lymph nodes of recipient mice were harvested after 12–15 h, and the percentage of WKO lymphocyte homing relative to WT was determined. Shown are averages ± SD of combined data from two experiments including eight (CD4+CD25−) and seven (nTreg cells) mice per group. Dashed line represents the input percentage.
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Related In: Results  -  Collection

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

fig3: Defective homing of WKO nTreg cells to peripheral lymphoid organs. (A) Reduced accumulation of WKO nTreg cells in the CD45RB transfer model. SCID mice were cotransferred with WT CD4+CD45RBhi and either WT (left) or WKO (right) nTreg cells. 10 wk after transfer, spleen, mesenteric lymph node, and colonic lamina propria cells were collected and stained for CD4 and Foxp3. Shown are representative dot plots of 6 and 10 mice per group. (B) nTreg cells or CD4+CD25− cells were isolated from peripheral lymphoid organs of WT and WKO mice, labeled with CFSE (WT) or TRITC (WKO), and mixed at a 1:1 ratio before intravenous injection to WT mice. Spleen and peripheral and mesenteric lymph nodes of recipient mice were harvested after 12–15 h, and the percentage of WKO lymphocyte homing relative to WT was determined. Shown are averages ± SD of combined data from two experiments including eight (CD4+CD25−) and seven (nTreg cells) mice per group. Dashed line represents the input percentage.
Mentions: We have previously demonstrated in vitro and in vivo that WKO mice have global defects in directed leukocyte migration (28). We hypothesized that the failure of WKO nTreg cells to suppress colitis in the CD45RB transfer model may result, at least in part, from defects in migration of WKO nTreg cells to target organs. Consistent with this hypothesis, the numbers of WKO nTreg cells recovered from the spleen, mesenteric lymph nodes, and lamina propria was reduced compared with WT nTreg cells in mice cotransferred with WT CD45RBhi T cells (Fig. 3 A).

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