T cell-mediated inhibition of the transfer of autoimmune diabetes in NOD mice.

Abstract

The nonobese diabetic (NOD)' mouse provides a relevant model for insulindependent diabetes mellitus (IDDM). Spontaneous IDDM is usually observed after 12 wk of age and largely predominates in females (1). The role of autoimmune phenomena in the destruction of islet (3 cells in this model is indicated by islet infiltration by mononuclear cells, mainly T lymphocytes (2, 3), by prevention ofIDDM by neonatal thymectomy (4), and by in vivo treatment with cyclosporine A (5), anti-CD4 + (6, 7), or anti-I-A mAbs (8). In addition, adoptive transfer of overt diabetes has recently been obtained both in healthy NOD neonates (9) and in pre-irradiated adult male recipients (10, 11) by injection of spleen cells collected from diabetic NOD mice . The need for irradiation in order to render nondiabetic adult NOD mice susceptible to diabetes transfer appears around 5 wk of age in females and around 3 wk of age in males (9). Diabetes transfer depends in both models on the simultaneous presence of CD4+ and CD8 + cells (9, 11). The role of T cells is further underlined by the predominance of Thy-1,2+ cells in islet infiltrates (3), the absence ofdiabetes in NOD nu/nu mice (12), and by efficient transfer of the disease in B cell-deprived recipients (13). Finally, it is worth noting that the NOD mouse disease shows a polygenic susceptibility that includes clear genetic linkage with genes mapping within the MHC (14-17).The role of regulatory T cells in the development ofantipancreatic autoimmunity remains unclear. Induction of early diabetes in young male as well as female NOD mice by injections ofcyclophosphamide (18) and the requirement for the pre-irradiation mentioned above to transfer IDDM into adult recipients (10), suggested a role of suppressive immune phenomena whose nature has remained elusive in other systems.The adoptive transfer model provides a sensitive assay for further establishing the existence of such suppressive phenomena and studying their mechanisms . In this study, we bring direct evidence for suppressor cells that inhibit the transfer of diabetes in 8-wk-old pre-irradiated NOD recipients . We show that suppressor cells in this model are age and sex dependent, are CD4+ cells, and are abrogated by thymectomy at 3 wk of age.

Increased islet antigen presentation leads to type‐1 diabetes in mice with autoimmune susceptibility

“…Interestingly, the number of autoreactive precursor T cells is similar between males and females but male lymphocytes are functionally less aggressive [36]. Furthermore, male NOD mice are more sensitive to the inhibitory activity of regulatory T cells than females [37]. The incidence of diabetes in male transgenic 8.3-NOD mice is lower than in females; however, similar numbers of autoreactive T cells populate their lymphoid organs [8].…”

Absence of significant Th2 response in diabetes-prone non-obese diabetic (NOD) mice

“…The absence of Th2 cells within the islet cell infiltrate was supported by experiments in which no IL-4-secreting T cells were detected within the islet infiltrate upon transfer of spleen cells from either 8-week-old or diabetic NOD mice into conventional recipients. Suppressive CD4 T cells were detected in 8-week-old NOD spleens [6,34] Spleen CD4 þ or CD8 þ T cells were purified from the spleens of diabetic female NOD mice. CD4-enriched T cells were composed of 73% CD4 þ /CD8 ¹ and 0·1% CD8 þ /CD4 ¹ cells; CD8-enriched T cells were composed of 52% CD8 þ /CD4 ¹ and 0·01% CD4 þ /CD8 ¹ cells.…”

Combined insulin B:9-23 self-peptide and polyinosinic–polycytidylic acid accelerate insulitis but inhibit development of diabetes by increasing the proportion of CD4+Foxp3+ regulatory T cells in the islets in non-obese diabetic mice

“…NOD mice only develop diabetes at 3 or 4 months of age, however, insulitis occurs long before the clinical onset of diabetes [18]. Disease transfer into irradiated recipients by spleen cells from diabetic NOD mice is prevented by CD4 + T cells from young pre-diabetic NOD mice were co-transferred with diabetogenic T cells [19]. Recent data have indicated that this protective effect is confined to a CD4 + CD25 + CD62L + Treg subset [20,21].…”

“…The B chain peptide, B:9-23, has been suggested to be a primary autoantigenic epitope in the pathogenesis of type 1 diabetes in NOD mice [4,5]. However, of interest, immunization of NOD mice with exogenous B: [9][10][11][12][13][14][15][16][17][18][19][20][21][22][23] peptide prevents diabetes [6].…”