title: Glucocorticoid-induced tumor necrosis factor receptor family-related protein regulates CD4(+)T cell-mediated colitis in mice.
abstract: OBJECTIVE
  The glucocorticoid-induced tumor necrosis factor receptor family-related protein (GITR; also called TNFRSF18 or CD357) regulates the T cell-mediated immune response and is present on surfaces of regulatory T (Treg) cells and activated CD4(+) T cells. We investigated the roles of GITR in the development of colitis in mice.
  
  
  METHODS
  Chronic enterocolitis was induced by the transfer of wild-type or GITR(-/-) CD4(+) T cells to GITR(-/-) × Rag(-/-) or Rag(-/-) mice. We determined the severity of colitis by using the disease activity index; measured levels of inflammatory cytokines, T cells, and dendritic cells; and performed histologic analysis of colon samples.
  
  
  RESULTS
  Transfer of nonfractionated CD4(+) cells from wild-type or GITR(-/-) donors induced colitis in GITR(-/-) × Rag(-/-) but not in Rag(-/-) mice. Among mice with transfer-induced colitis, the percentage of Treg and T-helper (Th) 17 cells was reduced but that of Th1 cells increased. Treg cells failed to prevent colitis in GITR(-/-) × Rag(-/-) recipients; this was not the result of aberrant function of GITR(-/-) Treg or T effector cells but resulted from an imbalance between the numbers of tolerogenic CD103(+) and PDCA1(+) plasmacytoid dendritic cells in GITR(-/-) mice. This imbalance impaired Treg cell development and expanded the Th1 population in GITR(-/-) × Rag(-/-) mice following transfer of nonfractionated CD4(+) cells.
  
  
  CONCLUSIONS
  GITR is not required on the surface of Treg and T effector cells to induce colitis in mice; interactions between GITR and its ligand are not required for induction of colitis. GITR instead appears to control dendritic cell and monocyte development; in its absence, mice develop aggravated chronic enterocolitis via an imbalance of colitogenic Th1 cells and Treg cells.
authors.affiliation: Division of Immunology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA. gliao@bidmc.harvard.edu
authors.forename: Gongxian
authors.initials: G
authors.lastname: Liao
authors.forename: Cynthia
authors.initials: C
authors.lastname: Detre
authors.forename: Scott B
authors.initials: SB
authors.lastname: Berger
authors.forename: Pablo
authors.initials: P
authors.lastname: Engel
authors.forename: Rene
authors.initials: R
authors.lastname: de Waal Malefyt
authors.forename: Roland W
authors.initials: RW
authors.lastname: Herzog
authors.forename: Atul K
authors.initials: AK
authors.lastname: Bhan
authors.forename: Cox
authors.initials: C
authors.lastname: Terhorst
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D049109:Cell Proliferation; D002478:Cells, Cultured; D002908:Chronic Disease; D003092:Colitis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D003106:Colon / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology; D004195:Disease Models, Animal; D053450:Glucocorticoid-Induced TNFR-Related Protein / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D039001:Integrin alpha Chains / Q000378:metabolism; D007413:Intestinal Mucosa / Q000276:immunology; D008024:Ligands; D008198:Lymph Nodes / Q000276:immunology; D017710:Lymphocyte Transfusion; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012720:Severity of Illness Index; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology; D058504:Th17 Cells / Q000276:immunology; D013997:Time Factors
chemical_list: D015703:Antigens, CD; D016207:Cytokines; D053450:Glucocorticoid-Induced TNFR-Related Protein; D018398:Homeodomain Proteins; D018836:Inflammation Mediators; D039001:Integrin alpha Chains; D008024:Ligands; C106544:Tnfrsf18 protein, mouse; C091367:alpha E integrins; C064658:RAG-1 protein