title: Intact Regulatory T-Cell Function but Defective Generation of IL-17A-Producing CD4+ T Cells in XIAP Deficiency.
abstract: 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-β signaling.
  
  
  
  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 xIAP 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 or WT Treg cells with naïve WT CD4 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 xIAP mice.
  
  
  
  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.
authors.affiliation: *Department of Pediatrics, Division of Gastroenterology †Department of Pediatrics, Division of Rheumatology, Medical College of Wisconsin, Milwaukee ‡Pediatric Rheumatology Division, University of Wisconsin School of Medicine and Public health, Madison §Department of Pediatrics, Section of Quantitative Health Sciences, Medical College of Wisconsin, Milwaukee.
authors.forename: Bhaskar
authors.initials: B
authors.lastname: Gurram
authors.forename: Erin
authors.initials: E
authors.lastname: Hammelev
authors.forename: Grant
authors.initials: G
authors.lastname: Syverson
authors.forename: Dipica
authors.initials: D
authors.lastname: Haribhai
authors.forename: Key
authors.initials: K
authors.lastname: Yan
authors.forename: Pippa
authors.initials: P
authors.lastname: Simpson
authors.forename: Nita
authors.initials: N
authors.lastname: Salzman
authors.forename: James W
authors.initials: JW
authors.lastname: Verbsky
mesh_terms: D000818:Animals; D002908:Chronic Disease; D003092:Colitis / Q000209:etiology* / Q000276:immunology; D040181:Genetic Diseases, X-Linked / Q000150:complications / Q000276:immunology*; D051034:Inhibitor of Apoptosis Proteins / Q000172:deficiency* / Q000276:immunology; D020381:Interleukin-17 / Q000276:immunology*; D008232:Lymphoproliferative Disorders / Q000150:complications / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000276:immunology
chemical_list: C107521:Birc4 protein, mouse; C098680:Il17a protein, mouse; D051034:Inhibitor of Apoptosis Proteins; D020381:Interleukin-17; D016212:Transforming Growth Factor beta