Impaired Mitogen-Induced Expression of High-Affinity Interleukin 2 Receptors on Spleen Cells From NOD/Shi/Kbe Mice

Abstract

The immune abnormalities of NOD mice, a model of human type I (insulin-dependent) diabetes, have been postulated to be T-lymphocyte dependent. We measured responsiveness to exogenous interleukin 2 (IL-2) and IL-2 production in spleen mononuclear cells from female NOD/Shi/Kbe mice after stimulating the cells with concanavalin A (ConA blasts) or phytohemagglutinin (PHA blasts). Exogenous IL-2 produced significantly lower proliferative responses in each blast from 3- and 10-wk-old NOD/Shi/Kbe mice than from control strains. IL-2 production in NOD/Shi/Kbe mice was inclined to decrease but not significantly compared with controls. Even sufficient amounts of recombinant IL-2 (rIL-2) or IL-1 (rIL-1), added with mitogens to the preculture medium, failed to provoke normal proliferative responses from NOD/Shi/Kbe mouse cells. To clarify the reason for this defect, we investigated the expression of IL-2 receptors (IL-2Rs) on mitogen-activated cells with anti-IL-2R monoclonal antibody (PC61) and radiolabeled IL-2. Cytofluorometry showed no significant difference between strains in the number of PC61+ ConA and PHA blasts. However, Scatchard analysis with 125I-labeled IL-2 showed that the number of high-affinity IL-2Rs (H-IL-2Rs), the mediators of the biological activity of IL-2, was decreased in NOD/Shi/Kbe mice compared with controls, whereas the number of low-affinity IL-2Rs (L-IL-2Rs) was not different. Separating the L3T4+ and Lyt-2+ populations of T lymphocytes by cell sorting showed both to be deficient in H-IL-2Rs.(ABSTRACT TRUNCATED AT 250 WORDS)

Interleukin 4 reverses T cell proliferative unresponsiveness and prevents the onset of diabetes in nonobese diabetic mice.

“…Second, the relative affinity (Kd) of HIL-2R for IL-2 and the number of HIL-2R molecules per cell on activated NOD and BALB/c thymic T cells are similar. This result differs from the previous report that HIL-2R expression is reduced about two-to threefold in mitogen-stimulated CD4 + and CD8 + spleen T cells from 10-wk-old NOD/ ShiKbe mice, and that this reduction might mediate the pathogenesis of type I diabetes in these mice (25). T cell responsiveness in the thymus of NOD/Del mice therefore does not appear to be due to a decrease in either the level of expression or binding affinity of HIL-2R on CD4 + or CD8 + T cells.…”

“…This unresponsiveness is not restored to normal by addition of physiological concentrations of exogenous rlL-2, and is at best only partially corrected by addition of supraphysiological amounts of rlL-2 (7; this report). A similar finding was reported for the inability of IL-2 to promote normal proliferative responses of Con A-stimulated NOD spleen T cells from 3-and 10-wk-old NOD/ShiKbe mice (25). These data are compatible with the observation that anergy can be induced in Thl cells as a consequence of TCR occupancy by Ag in the absence of cell division (9).…”

“…Alternatively, if such TCR stimulation results in a decrease in or lack of expression of HIL-2R, then T cell proliferative unresponsiveness ensues (24). In Con A-activated CD4 + and CD8 + spleen T cells from 10-wk-old NOD/ShiKbe mice, HIL-2R expression is reduced about threefold (25). The latter result raised the possibility that the proliferative unresponsiveness of NOD thymocytes from >7-wk-old mice to Con A stimulation (7) is mediated by a diminished expression of HIL-2R.…”

Faulty Major Histocompatibility Complex Class II I-E Expression is Associated With Autoimmunity in Diverse Strains of Mice: Autoantibodies, Insulitis, and Sialadenitis

“…The penetrance of pathology secondary to a defect in this gene appears to occur independently of a given major histocompatibility complex haplotype or background murine strain and for these murine models, does not lead to diabetic hyperglycemia. Diabetes 42:1166-72,1993 T he NOD mouse is a well-studied murine model for type I diabetes (1)(2)(3)(4)(5)(6)(7). The first lymphoid infiltrates surround islets of Langerhans, as well as salivary glands, at ~2 mo of age; invasion of islets and salivary glands by these infiltrates, accompanied by autoantibody production and frank diabetes, is apparent by 6 mo of age in 70-80% of female mice.…”