B7 interactions with CD28 and CTLA-4 control tolerance or induction of mucosal inflammation in chronic experimental colitis.
CD28-B7 interaction plays a critical costimulatory role in inducing T cell activation, while CTLA-4-B7 interaction provides a negative signal that is essential in immune homeostasis. Transfer of CD45RB(high)CD4(+) T cells from syngeneic mice induces transmural colon inflammation in SCID recipients. This adoptive transfer model was used to investigate the contribution of B7-CD28/CTLA-4 interactions to the control of intestinal inflammation. CD45RB(high)CD4(+) cells from CD28(-/-) mice failed to induce mucosal inflammation in SCID recipients. Administration of anti-B7.1 (but not anti-B7.2) after transfer of wild-type CD45RB(high)CD4(+) cells also prevented wasting disease with colitis, abrogated leukocyte infiltration, and reduced production of proinflammatory cytokines IL-2 and IFN-gamma by lamina propria CD4(+) cells. In contrast, anti-CTLA-4 treatment led to deterioration of disease, to more severe inflammation, and to enhanced production of proinflammatory cytokines. Of note, CD25(+)CD4(+) cells from CD28(-/-) mice similar to those from the wild-type mice were efficient to prevent intestinal mucosal inflammation induced by the wild-type CD45RB(high) cells. The inhibitory functions of these regulatory T cells were effectively blocked by anti-CTLA-4. These data show that the B7-CD28 costimulatory pathway is required for induction of effector T cells and for intestinal mucosal inflammation, while the regulatory T cells function in a CD28-independent way. CTLA-4 signaling plays a key role in maintaining mucosal lymphocyte tolerance, most likely by activating the regulatory T cells.
Liu
Z
Z
Laboratory of Experimental Immunology, Department of Pathology, University Hospital Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium.
Geboes
K
K
Hellings
P
P
Maerten
P
P
Heremans
H
H
Vandenberghe
P
P
Boon
L
L
van Kooten
P
P
Rutgeerts
P
P
Ceuppens
J L
JL
D000069594:Abatacept; D019264:Adoptive Transfer; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D015703:Antigens, CD / Q000096:biosynthesis / Q000276:immunology / Q000502:physiology*; D000943:Antigens, Differentiation / Q000276:immunology / Q000502:physiology*; D018122:B7-1 Antigen / Q000096:biosynthesis / Q000276:immunology / Q000502:physiology*; D051940:B7-2 Antigen; D018106:CD28 Antigens / Q000235:genetics / Q000502:physiology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000637:transplantation; D060908:CTLA-4 Antigen; D003092:Colitis / Q000209:etiology / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D003106:Colon / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D006224:Cricetinae; D005260:Female; D007106:Immune Sera / Q000008:administration & dosage; D007108:Immune Tolerance / Q000276:immunology*; D018796:Immunoconjugates; D007274:Injections, Intraperitoneal; D007413:Intestinal Mucosa / Q000276:immunology* / Q000473:pathology*; D017493:Leukocyte Common Antigens / Q000096:biosynthesis; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000276:immunology / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D016513:Mice, SCID; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism / Q000637:transplantation
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000943:Antigens, Differentiation; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; C497965:Cd86 protein, mouse; C556707:Ctla4 protein, mouse; D007106:Immune Sera; D018796:Immunoconjugates; D008562:Membrane Glycoproteins; D015375:Receptors, Interleukin-2; D000069594:Abatacept; D017493:Leukocyte Common Antigens