Intact regulatory T-Cell function but defective generation of IL-17A-producing CD4+ T cells in XIAP deficiency

Bhaskar Gurram, Erin Hammelev, Grant Syverson, Dipica Haribhai, Key Yan, Pippa Simpson, Nita Salzman, James W. Verbsky

Research output: Contribution to journalArticle

Abstract

Objective: X-linked inhibitor of apoptosis (xIAP) deficiency is a primary immune deficiency disorder associated with hemophagocytic lymphohistiocytosis. About 17% of xIAP-deficient patients present with very early onset severe colitis with high mortality. We hypothesized that xIAP deficiency leads to defective generation and/or survival of T regulatory cells (Treg) through its involvement in transforming growth factor-b signaling. Methods and Results: We used a T-cell transfer model of chronic colitis and observed a mild increase in colitis severity induced by naïve CD4+ T cells from xIAP0/- mice compared with colitis induced by naïve CD4+ T cells from WT mice. We did not observe any significant difference in the induction of Treg cells in these studies. We next tested whether xIAP is required for Treg cell function by co-transferring xIAP-/0 or WT Treg cells with naïve WTCD4 cells in this model. We demonstrate that XIAP-deficient Treg cells were able to prevent disease similarly to WT Treg cells. In these experiments we, however, found a significantly decreased percentage of IL- 17A-producing CD4+ T cells in mice receiving Tregs from xIAP0/- mice. Conclusions: xIAP appears dispensable for the generation of induced Treg cells as well as function of natural Treg cells. There appeared to be a role of xIAP in generation of IL-17-producing cells from either naïve CD4+ T cells or Treg cells. Further research is needed to explore the role of xIAP in generation of IL-17-producing cells.

Original languageEnglish (US)
Pages (from-to)218-225
Number of pages8
JournalJournal of Pediatric Gastroenterology and Nutrition
Volume63
Issue number2
DOIs
StatePublished - Jul 26 2016

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Interleukin-17
Regulatory T-Lymphocytes
T-Lymphocytes
Apoptosis
Colitis
Lymphoproliferative Syndrome, X-Linked, 2
Hemophagocytic Lymphohistiocytosis
Immune System Diseases
Transforming Growth Factors

Keywords

  • Experimental colitis
  • Regulatory T cells
  • X-linked inhibitor of apoptosis protein

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Gastroenterology

Cite this

Intact regulatory T-Cell function but defective generation of IL-17A-producing CD4+ T cells in XIAP deficiency. / Gurram, Bhaskar; Hammelev, Erin; Syverson, Grant; Haribhai, Dipica; Yan, Key; Simpson, Pippa; Salzman, Nita; Verbsky, James W.

In: Journal of Pediatric Gastroenterology and Nutrition, Vol. 63, No. 2, 26.07.2016, p. 218-225.

Research output: Contribution to journalArticle

Gurram, Bhaskar ; Hammelev, Erin ; Syverson, Grant ; Haribhai, Dipica ; Yan, Key ; Simpson, Pippa ; Salzman, Nita ; Verbsky, James W. / Intact regulatory T-Cell function but defective generation of IL-17A-producing CD4+ T cells in XIAP deficiency. In: Journal of Pediatric Gastroenterology and Nutrition. 2016 ; Vol. 63, No. 2. pp. 218-225.
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abstract = "Objective: X-linked inhibitor of apoptosis (xIAP) deficiency is a primary immune deficiency disorder associated with hemophagocytic lymphohistiocytosis. About 17{\%} of xIAP-deficient patients present with very early onset severe colitis with high mortality. We hypothesized that xIAP deficiency leads to defective generation and/or survival of T regulatory cells (Treg) through its involvement in transforming growth factor-b signaling. Methods and Results: We used a T-cell transfer model of chronic colitis and observed a mild increase in colitis severity induced by na{\"i}ve CD4+ T cells from xIAP0/- mice compared with colitis induced by na{\"i}ve CD4+ T cells from WT mice. We did not observe any significant difference in the induction of Treg cells in these studies. We next tested whether xIAP is required for Treg cell function by co-transferring xIAP-/0 or WT Treg cells with na{\"i}ve WTCD4 cells in this model. We demonstrate that XIAP-deficient Treg cells were able to prevent disease similarly to WT Treg cells. In these experiments we, however, found a significantly decreased percentage of IL- 17A-producing CD4+ T cells in mice receiving Tregs from xIAP0/- mice. Conclusions: xIAP appears dispensable for the generation of induced Treg cells as well as function of natural Treg cells. There appeared to be a role of xIAP in generation of IL-17-producing cells from either na{\"i}ve CD4+ T cells or Treg cells. Further research is needed to explore the role of xIAP in generation of IL-17-producing cells.",
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AU - Gurram, Bhaskar

AU - Hammelev, Erin

AU - Syverson, Grant

AU - Haribhai, Dipica

AU - Yan, Key

AU - Simpson, Pippa

AU - Salzman, Nita

AU - Verbsky, James W.

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N2 - Objective: X-linked inhibitor of apoptosis (xIAP) deficiency is a primary immune deficiency disorder associated with hemophagocytic lymphohistiocytosis. About 17% of xIAP-deficient patients present with very early onset severe colitis with high mortality. We hypothesized that xIAP deficiency leads to defective generation and/or survival of T regulatory cells (Treg) through its involvement in transforming growth factor-b signaling. Methods and Results: We used a T-cell transfer model of chronic colitis and observed a mild increase in colitis severity induced by naïve CD4+ T cells from xIAP0/- mice compared with colitis induced by naïve CD4+ T cells from WT mice. We did not observe any significant difference in the induction of Treg cells in these studies. We next tested whether xIAP is required for Treg cell function by co-transferring xIAP-/0 or WT Treg cells with naïve WTCD4 cells in this model. We demonstrate that XIAP-deficient Treg cells were able to prevent disease similarly to WT Treg cells. In these experiments we, however, found a significantly decreased percentage of IL- 17A-producing CD4+ T cells in mice receiving Tregs from xIAP0/- mice. Conclusions: xIAP appears dispensable for the generation of induced Treg cells as well as function of natural Treg cells. There appeared to be a role of xIAP in generation of IL-17-producing cells from either naïve CD4+ T cells or Treg cells. Further research is needed to explore the role of xIAP in generation of IL-17-producing cells.

AB - Objective: X-linked inhibitor of apoptosis (xIAP) deficiency is a primary immune deficiency disorder associated with hemophagocytic lymphohistiocytosis. About 17% of xIAP-deficient patients present with very early onset severe colitis with high mortality. We hypothesized that xIAP deficiency leads to defective generation and/or survival of T regulatory cells (Treg) through its involvement in transforming growth factor-b signaling. Methods and Results: We used a T-cell transfer model of chronic colitis and observed a mild increase in colitis severity induced by naïve CD4+ T cells from xIAP0/- mice compared with colitis induced by naïve CD4+ T cells from WT mice. We did not observe any significant difference in the induction of Treg cells in these studies. We next tested whether xIAP is required for Treg cell function by co-transferring xIAP-/0 or WT Treg cells with naïve WTCD4 cells in this model. We demonstrate that XIAP-deficient Treg cells were able to prevent disease similarly to WT Treg cells. In these experiments we, however, found a significantly decreased percentage of IL- 17A-producing CD4+ T cells in mice receiving Tregs from xIAP0/- mice. Conclusions: xIAP appears dispensable for the generation of induced Treg cells as well as function of natural Treg cells. There appeared to be a role of xIAP in generation of IL-17-producing cells from either naïve CD4+ T cells or Treg cells. Further research is needed to explore the role of xIAP in generation of IL-17-producing cells.

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