title: Cytotoxic-T-lymphocyte-associated antigen 4 blockade abrogates protection by regulatory T cells in a mouse model of microbially induced innate immune-driven colitis.
abstract: Cytotoxic-T-lymphocyte-associated antigen 4 (CTLA-4) expressed at high levels by CD4(+) CD25(+) CD45RB(low) regulatory T cells (Treg) is essential to their homeostatic and immunoregulatory functions. However, its relevance to anti-inflammatory roles of Treg in the context of colitogenic innate immune response during pathogenic bacterial infections has not been examined. We showed earlier in Rag2-deficient 129/SvEv mice that Treg cells are capable of suppressing colitis and colon cancer triggered by Helicobacter hepaticus, a widespread murine enterohepatic pathogen. Using this model, we now examined the effects of antibody blockade of CTLA-4 on Treg function during innate immune inflammatory response. Consistent with our previous findings, we found that a single adoptive transfer of Treg cells prior to infection prevented colitis development despite persistent H. hepaticus infection in recipient mice. However, when infected mice were injected with anti-CTLA-4 antibody along with Treg cell transfer, they developed a severe acute colitis with poor body condition that was not observed in Rag2(-/-) mice without Treg cell transfer. Despite high numbers of Foxp3(+) Treg cells, evident by immunohistochemical analyses in situ, the CTLA-4 antibody-treated mice had severely inflamed colonic mucosa and increased rather than decreased expression levels of cytokines gamma interferon and interleukin-2. These findings indicate that antibody blockade of CTLA-4 clearly abrogates Treg cell ability to suppress innate immune-driven colitis and suggest that Treg cell CTLA-4 cognate interactions may be necessary to maintain homeostasis among cells of innate immunity.
authors.affiliation: Division of Comparative Medicine, Massachusetts Institute of Technology, 77 Massachusetts Ave., Cambridge, MA 02139, USA.
authors.forename: Koichiro
authors.initials: K
authors.lastname: Watanabe
authors.forename: Varada P
authors.initials: VP
authors.lastname: Rao
authors.forename: Theofilos
authors.initials: T
authors.lastname: Poutahidis
authors.forename: Barry H
authors.initials: BH
authors.lastname: Rickman
authors.forename: Masahiro
authors.initials: M
authors.lastname: Ohtani
authors.forename: Shilu
authors.initials: S
authors.lastname: Xu
authors.forename: Arlin B
authors.initials: AB
authors.lastname: Rogers
authors.forename: Zhongming
authors.initials: Z
authors.lastname: Ge
authors.forename: Bruce H
authors.initials: BH
authors.lastname: Horwitz
authors.forename: Toshio
authors.initials: T
authors.lastname: Fujioka
authors.forename: Susan E
authors.initials: SE
authors.lastname: Erdman
authors.forename: James G
authors.initials: JG
authors.lastname: Fox
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D015703:Antigens, CD / Q000276:immunology*; D060908:CTLA-4 Antigen; D003092:Colitis / Q000276:immunology* / Q000473:pathology; D004268:DNA-Binding Proteins / Q000172:deficiency; D044923:Helicobacter hepaticus; D007113:Immunity, Innate; D007150:Immunohistochemistry; D007371:Interferon-gamma / Q000096:biosynthesis; D007376:Interleukin-2 / Q000096:biosynthesis; D051379:Mice; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D015703:Antigens, CD; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D004268:DNA-Binding Proteins; D007376:Interleukin-2; C499308:Rag2 protein, mouse; D007371:Interferon-gamma