BCD4 T Cells as Direct Effectors of pCell Lysis

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Immunohistochemical examination of the pancreata of patients with IDDM who died early in the course of the disease revealed that the p cells aberrantly expressed class II MHC molecules (16). This led to the hypothesis that class II MHC-restricted autoreactive CD4+ T cells (which have been identified against many islet cell proteins) could act as the effector cells, recognizing antigenic peptides derived from a p-cell-specific antigen. It was considered that these CD4+ T cells would not have been subject to thymic tolerance mechanisms (17). This view has the attraction of unifying the known genetic susceptibility conferred by class II MHC haplotypes with experimental data concerning p-cell antigen-specific CD4+ autoreactive T cells.

A transgenic mouse model in which allogeneic MHC class II expression is limited to p cells using a rat insulin promoter did not support this hypothesis (18). The mice expressed allogeneic class II MHC on the p cells but did not develop insulitis or IDDM. Potentially autoreactive CD4+ T cells were rendered anergic. However, this model is an incomplete test of the hypothesis, as the p cells did not express the necessary costimulator molecules (19), such as B7 (CD80) or B7-2, and MHC class II-associated invariant chain (Ii) (20) was not included in the transgenic model.

Recent evidence in a triple transgenic model shows that expression of the B7 molecule on the P cells was critical in the activation of autoreactive T cells (21). The model used the rat insulin promoter to direct expression of a viral protein, lymphocytic choriomeningitis virus (LCMV) cell surface glycoprotein, and B7 to the p cells, and a transgenic T-cell receptor (TCR) which skews the T-cell repertoire exclusively to express a TCR specific for an epitope of the viral glycoprotein. Although the double transgenic TCR/viral protein mice required external activation in the form of infection by the LCMV (22), the triple transgenic mice spontaneously develop IDDM.

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