Low interleukin-2 synthesis by type 1 diabetics is regulated at the pretranslational level.
Insulin-dependent diabetes mellitus (IDDM) is believed to be a consequence of an autoimmune attack on beta cells by T cells. We have previously reported that T cells from the majority of patients with IDDM produced decreased levels of interleukin-2 (IL-2) following activation with phytohemagglutinin. In this study we began to characterize the basis for this defect. First, we tested whether the decreased IL-2 synthesis was due to the secretion of a factor which inhibited the ability of indicator cells to respond to IL-2 or which inhibited IL-2 release by responder cells. Second, we examined steady-state levels of IL-2 mRNA in IDDMs and controls. To make this feasible, given the limited number of peripheral blood lymphocytes (PBL) available from our patients, we depended upon an approach which enabled the generation of large numbers of resting T cells, called G0/G1 cells, from small numbers of PBL. Preliminary experiments demonstrated that G0/G1 cells from IDDMs reproduced the IL-2 defect seen originally with PBL. Our results suggested that the secretion of inhibitory factors could not explain the IL-2 defect. A comparison of steady-state levels of IL-2 mRNA from activated T cells of IDDMs and age-matched controls, however, demonstrated lower levels of IL-2 mRNA in IDDMs compared to controls. Finally, we observed that the IL-2 mRNA in IDDM T cells was less stabile than that in the control cells, suggesting a possible mechanism for the defect.
Shah
U
U
Department of Medicine, Mt. Sinai School of Medicine, New York, New York 10029.
Karch
L
L
Baker
L
L
Zier
K S
KS
D000293:Adolescent; D002648:Child; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism*; D005260:Female; D016193:G1 Phase; D006801:Humans; D007376:Interleukin-2 / Q000096:biosynthesis* / Q000235:genetics; D008297:Male; D012333:RNA, Messenger / Q000032:analysis; D016192:Resting Phase, Cell Cycle; D013601:T-Lymphocytes / Q000378:metabolism
D007376:Interleukin-2; D012333:RNA, Messenger