Autoimmunity, or the recognition and destruction of self-tissues by immune effector cells, is the result of a breakdown in peripheral tolerance. Determining how self-reactive cells are kept in check is important to understanding disease pathogenesis. The recent identification of the B7x molecule indicates a new mechanism by which peripheral tolerance can be maintained as in vitro experiments demonstrate that B7x inhibits T cell proliferation and cytokine production. However, unlike the other members of the B7 family, there is very low expression of B7x in the hematopoietic compartment. We examined both murine and human B7x expression and observed that there is either very low mRNA or no protein B7x expression on T cells, B cells, dendritic cells, and macrophages, even after culturing these cell types in various stimulating and maturation conditions. However, B7x mRNA and protein is highly expressed in a broad range of peripheral organs, indicating that the molecule is present in the proper tissues to inhibit T cell mediated autoimmunity.
Immunohistochemical staining shows that B7x expression is restricted to pancreatic islets suggesting that B7x may have a role in inhibiting diabetogenic T cells. Therefore, we examined whether the overexpression of B7x could inhibit the development of an aggressive form of diabetes. Crossing diabetes susceptible BDC2.5 transgenic mice to mice overexpressing B7x under the rat insulin promoter (RipB7x) results in a complete abrogation of disease. This inhibitory function of B7x in vivo is supported by the observation that when activated BDC2.5 T cells are transferred into RipB7x mice, there are fewer BDC2.5 T cells infiltrating the pancreata, and that a smaller fraction of these cells produce IFN-γ in comparison to transgene negative controls. To determine whether endogenous B7x has an inhibitory role in autoimmunity, we induced EAE in B7x-deficient mice. On the 129/SvE background, B7x knockout mice reproducibly exhibit more severe disease, which is reflected in the increased absolute numbers of Th1, Th17, and activated CD4 T cells in the CNS in comparison to wildtype mice. The results from these two autoimmunity models indicate that B7x has a role in maintaining tolerance against self-reactive immune cells.
|Advisor:||Allison, James, Sha, William|
|School:||University of California, Berkeley|
|School Location:||United States -- California|
|Source:||DAI-B 70/04, Dissertation Abstracts International|
|Keywords:||Autoimmunity, Costimulation, Diabetes, Peripheral tolerance|
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