INTERLEUKIN-4 REVERSES T-CELL PROLIFERATIVE UNRESPONSIVENESS AND PREVENTS THE ONSET OF DIABETES IN NONOBESE DIABETIC MICE

Beginning at the time of insulitis (7 wk of age), CD4+ and CD8+ mature thymocytes from nonobese diabetic (NOD) mice exhibit a proliferative unresponsiveness in vitro after T cell receptor (TCR) crosslinking. Th is unresponsiveness does not result from either insulitis or thymic in volution and is long lasting, i.e., persists until diabetes onset (24 wk of age). We previously proposed that it represents a form of thymic T cell anergy that predisposes to diabetes onset. This hypothesis was tested in the present study by further investigating the mechanism re sponsible for NOD thymic T cell proliferative unresponsiveness and det ermining whether reversal of this unresponsiveness protects NOD mice f rom diabetes. Interleukin 4 (IL-4) secretion by thymocytes from >7-wk- old NOD mice was virtually undetectable after treatment with either an ti-TCR alpha/beta, anti-CD3, or Concanavalin A (Con A) compared with t hose by thymocytes from age- and sex-matched control BALB/c mice stimu lated under identical conditions. NOD thymocytes stimulated by anti-TC R alpha/beta or anti-CD3 secreted less IL-2 than did similarly activat ed BALB/c thymocytes. However, since equivalent levels of IL-2 were se creted by Con A-activated NOD and BALB/c thymocytes, the unresponsiven ess of NOD thymic T cells does not appear to be dependent on reduced I L-2 secretion. The surface density and dissociation constant of the hi gh affinity IL-2 receptor of Con A-activated thymocytes from both stra ins are also similar. The patterns of unresponsiveness and lymphokine secretion seen in anti-TCR/CD3-activated NOD thymic T cells were also observed in activated NOD peripheral spleen T cells. Exogenous recombi nant (r)IL-2 only partially reverses NOD thymocyte proliferative unres ponsiveness to anti-CD3, and this is mediated by the inability of IL-2 to stimulate a complete IL-4 secretion response. In contrast, exogeno us rIL-4 reverses the unresponsiveness of both NOD thymic and peripher al T cells completely, and this is associated with the complete restor ation of an IL-2 secretion response. Furthermore, the in vivo administ ration of rIL-4 to prediabetic NOD mice protects them from diabetes. T hus, the ability of rIL-4 to reverse completely the NOD thymic and per ipheral T cell proliferative defect in vitro and protect against diabe tes in vivo provides further support for a causal relationship between this T cell proliferative unresponsiveness and susceptibility to diab etes in NOD mice.