A diabetogenic gene prevents T cells from receiving costimulatory signals.
T cell fate following antigen encounter is determined by several intracellular signals generated by the interaction of the T cell with an antigen-presenting cell. In the periphery activation requires T cell receptor signaling (signal one) in combination with costimulatory signals (signal two), usually provided through the cognate interaction of CD28 and B7 molecules. Provision of signal one alone to purified murine peripheral T cells in vitro induces apoptosis or anergy rather than promoting activation. These T cells can be rescued from apoptosis if they are provided with costimulation supplied, for example, by engaging the CD28 co-receptor with an anti-CD28 monoclonal antibody or by adding an exogenous source of interleukin-2. However, a majority of peripheral T cells from autoimmune, diabetes-prone Biobreeding (BB) rats exhibited different responses to these stimuli. T cells from these rats could not be rescued from apoptosis by costimulation. This was not due to the inability of BB-DP T cells to upregulate CD28 and the IL-2 receptor in response to TCR crosslinking. The failure of these costimulatory interactions to rescue BB-DP T cells segregated with the diabetes-susceptibility gene iddm1. Iddm1 in the rat causes peripheral T cell lymphopenia, which is associated with a dramatically shortened peripheral T cell life span. Our results indicate that a diabetogenic gene may contribute to autoimmunity by negating costimulatory signals important for the survival of long-lived peripheral T cells.
Moore
J K
JK
Department of Immunology, Department of Medicine, University of Colorado Health Sciences Center, 4200 E. Ninth Avenue, Denver, Colorado, 80262, USA.
Gold
D P
DP
Dreskin
S C
SC
Lernmark
A
A
Bellgrau
D
D
D000818:Animals; D018106:CD28 Antigens / Q000276:immunology; D003208:Concanavalin A / Q000494:pharmacology; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology*; D016130:Immunophenotyping; D008934:Mitogens / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D015375:Receptors, Interleukin-2 / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology*; D018800:Thy-1 Antigens / Q000276:immunology
D018106:CD28 Antigens; D008934:Mitogens; D011948:Receptors, Antigen, T-Cell; D015375:Receptors, Interleukin-2; D018800:Thy-1 Antigens; D003208:Concanavalin A