ROLE OF CD4-CELLS IN THE DEVELOPMENT OF AUTOIMMUNE DIABETES IN THE NONOBESE DIABETIC (NOD) MOUSE(CD45RA+ T)

The non-obese diabetic (NOD) mouse spontaneously develops a T cell-med iated autoimmune disease, sharing many features with human insulin-dep endent diabetes mellitus (IDDM), leading to insulin-secreting beta cel l destruction. The role of CD4+ T cells has been evidenced at two leve ls. First, CD4+ T cells from diabetic animals are required to transfer diabetes to non-diabetic recipients in conjunction with CD8+ effector T cells. Second, suppressive CD4+ T cells have been characterized in non-diabetic NOD mice. T cells with different functions can thus share the CD4+ phenotype. Since CD4+ T cells can be divided into at least t wo subgroups on the basis of CD45 isoform expression, we evaluated the distribution of CD4+ T cells expressing the CD45RA isoform on NOD mou se thymocytes and peripheral T cells. The percentage of CD45RA+ cells was dramatically increased among the most mature CD3bright thymocytes and among CD4+ T cells in lymph nodes of the NOD mouse as compared wit h control strains. This increase was related to the development of ins ulitis. Interestingly, the CD45RA isoform was expressed on most CD4+ T cells invading the islets. In vivo treatment with an anti-CD45RA mAb prevented the development of insulitis and spontaneous diabetes in fem ale animals but not the transfer of diabetes by T cells collected from diabetic NOD donors. These results indicate that anti-CD45RA mAb is o nly effective if given before the full commitment of effector T cells to the destruction of islet beta cells. Thus CD4+CD45RA+ T cells play a key role in early activation steps of anti-islet immunity.