A diabetogenic gene prevents T cells from receiving costimulatory signals

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A diabetogenic gene prevents T cells from receiving costimulatory signals. / Moore, Jodene K.; Gold, Daniel P.; Dreskin, Stephen C.; Lernmark, Åke; Bellgrau, Donald.

In: Cellular Immunology, Vol. 194, No. 1, 25.05.1999, p. 90-97.

Research output: Contribution to journalArticle

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Moore, Jodene K. ; Gold, Daniel P. ; Dreskin, Stephen C. ; Lernmark, Åke ; Bellgrau, Donald. / A diabetogenic gene prevents T cells from receiving costimulatory signals. In: Cellular Immunology. 1999 ; Vol. 194, No. 1. pp. 90-97.

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TY - JOUR

T1 - A diabetogenic gene prevents T cells from receiving costimulatory signals

AU - Moore, Jodene K.

AU - Gold, Daniel P.

AU - Dreskin, Stephen C.

AU - Lernmark, Åke

AU - Bellgrau, Donald

PY - 1999/5/25

Y1 - 1999/5/25

N2 - 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.

AB - 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.

U2 - 10.1006/cimm.1999.1501

DO - 10.1006/cimm.1999.1501

M3 - Article

C2 - 10357884

AN - SCOPUS:0033603027

VL - 194

SP - 90

EP - 97

JO - Cellular Immunology

JF - Cellular Immunology

SN - 0008-8749

IS - 1

ER -