A diabetogenic gene prevents T cells from receiving costimulatory signals

T cell fate following antigen encounter is determined by several intracellu lar signals generated by the interaction of the T cell with an antigen-pres enting cell. In the periphery activation requires T cell receptor signaling (signal one) in combination with costimulatory signals (signal two), usual ly provided through the cognate interaction of CD28 and B7 molecules. Provi sion of signal one alone to purified murine peripheral T cells in vitro ind uces apoptosis or anergy rather than promoting activation. These T cells ca n be rescued from apoptosis if they are provided with costimulation supplie d, for example, by engaging the CD28 co-receptor with an anti-CD28 monoclon al antibody or by adding an exogenous source of interleukin-a. However, a m ajority 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 du e to the inability of BB-DP T cells to upregulate CD28 and the IL-2 recepto r in response to TCR crosslinking. The failure of these costimulatory inter actions to rescue BB-DP T cells segregated with the diabetes-susceptibility gene iddm1. Iddm1 in the rat causes peripheral T cell lymphopenia, which i s associated with a dramatically shortened peripheral T cell life span. Our results indicate that a diabetogenic gene may contribute to autoimmunity b y negating costimulatory signals important for the survival of long-lived p eripheral T cells. (C) 1999 Academic Press.