A key role for ICAM-1 in generating effector cells mediating inflammatory responses.
We investigated how the accessory molecule interactions encountered during T cell priming influence T cell-mediated destruction of insulin-producing beta cells and lead to type 1 diabetes. T cell receptor (TCR)-transgenic CD4+ T cells were primed under controlled conditions in vitro before being adoptively transferred into transgenic recipients expressing membrane ovalbumin under the control of the rat insulin promoter (RIP-mOVA). During priming, antigen-presenting cell expression of B7-1 without intracellular adhesion molecule 1 (ICAM-1) led to the generation of effector cells that migrated to the pancreata of RIP-mOVA recipients but did not cause diabetes. In contrast, when T cells were primed with APCs expressing both B7-1 and ICAM-1, pronounced destruction of beta cells and a rapid onset of diabetes were observed. Pathogenicity was associated with T cell production of the macrophage-attracting chemokines CCL3 and CCL4. Thus, interactions of lymphocyte function-associated antigen 1 with ICAM-1 during priming induce both qualitative and quantitative alterations in T effector function and induce potentially autodestructive responses.
Camacho
S A
SA
Department of Immunology, IMM4, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Heath
W R
WR
Carbone
F R
FR
Sarvetnick
N
N
LeBon
A
A
Karlsson
L
L
Peterson
P A
PA
Webb
S R
SR
D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D018122:B7-1 Antigen / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000209:etiology / Q000276:immunology / Q000473:pathology; D066298:In Vitro Techniques; D007249:Inflammation / Q000209:etiology* / Q000276:immunology / Q000473:pathology; D007328:Insulin / Q000235:genetics; D018799:Intercellular Adhesion Molecule-1 / Q000276:immunology*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic; D051381:Rats; D011948:Receptors, Antigen, T-Cell / Q000235:genetics
D018122:B7-1 Antigen; D007328:Insulin; D016169:Lymphocyte Function-Associated Antigen-1; D011948:Receptors, Antigen, T-Cell; D018799:Intercellular Adhesion Molecule-1