B7-1 mediated costimulation regulates pancreatic autoimmunity.
Costimulation by B7-1 and B7-2 molecules results in divergent biological effects. This is particularly striking in the NOD mouse, since the lack of B7-2 leads to complete protection from diabetes whereas the B7-1 deficiency causes exacerbation of disease. We tested the hypothesis that B7-1 costimulation suppresses pancreatic autoimmunity. We describe that the lack of B7-1 not only causes aberrant thymocyte maturation but also significantly enhances expansion, survival, and effector function of islet specific T cells in periphery. We also observed a significant reduction in the proportion of T-regulatory (T-regs) cells. Immunophenotypic analysis of T and APCs revealed a significantly lower frequency of T cells expressing the negative costimulatory receptor PD-1 in B7-1KO mice whereas the proportion of B7-H1 positive APCs was found to be significantly higher. Blocking studies in B7-1KO mice suggest that B7-H1 provides negative signals for anti islet CD4 and CD8 T-cell expansion but is differentially required for their priming. Our data demonstrate that deficiency of B7-1 mediated costimulation causes multitude of immunological defects, which involve reduction in T-regs and a concomitant enhancement of expansion, survival and effector potential of auto reactive T cells.
Yadav
Deepak
D
The Scripps Research Institute, Department of Immunology, 10550 North Torrey Pines Road, Mail Drop IMM-23, La Jolla, CA 92037, USA.
Fine
Cody
C
Azuma
Miyuki
M
Sarvetnick
Nora
N
D000818:Animals; D000943:Antigens, Differentiation / Q000032:analysis / Q000276:immunology; D015551:Autoimmunity / Q000235:genetics*; D018122:B7-1 Antigen / Q000235:genetics / Q000502:physiology*; D018106:CD28 Antigens / Q000032:analysis / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002470:Cell Survival; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D005260:Female; D007515:Islets of Langerhans / Q000276:immunology*; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D010179:Pancreas / Q000276:immunology*; D061026:Programmed Cell Death 1 Receptor
D000943:Antigens, Differentiation; D018122:B7-1 Antigen; D018106:CD28 Antigens; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor