Getting with the program in type 1 diabetes mellitus

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Science Immunology  05 Jan 2018:
Vol. 3, Issue 19, eaar8621
DOI: 10.1126/sciimmunol.aar8621


Transcriptomic studies reveal defective costimulation via PD-L1 to explain the autoreactive phenotype seen in type 1 diabetes mellitus.

Type 1 diabetes mellitus (T1D) begins with autoimmune destruction of insulin producing cells in the pancreas, usually in children. Although many immunosuppressive strategies have failed, the recent use of autologous hematopoietic stem and progenitor cell (HSPC) transplantation has shown therapeutic promise. Because PD-L1/programmed cell death (PD-1) deficiency accelerates development of diabetes in mouse models, Nasr et al. hypothesized that a defect in the PD-L1/PD-1 pathway may underpin the hyperglycemia observed in the nonobese diabetic (NOD) mouse model. They performed transcriptional profiling of HSPCs from NOD mice, which revealed decreased PD-L1 expression confined to HSPCs, compared with C57BL/6 controls. Reduced PD-L1 was confirmed by reverse transcription–polymerase chain reaction (RT-PCR), confocal microscopy, and Western blotting. Forty-eight microRNAs were differentially expressed between HSPCs from NOD and C57BL/6 mice, 14 of which regulated PD-L1 expression. In vitro experiments demonstrated an immunoregulatory function of transgenic PD-L1 overexpressing HSPCs. Adoptive transfer of these cells resulted in reversion of the hyperglycemic state in NOD mice, with reduced T cell infiltrates in the pancreas and increased circulating FoxP3+ regulatory T cells. Furthermore, the transgenic HSPCs were found to preferentially home to the pancreata of hyperglycemic mice. Similar beneficial effects were demonstrated with pharmacologically modulated HSPCs, both in vitro and in vivo.

Notably, a comparable PD-L1 defect was demonstrated in humans with T1D. PD-L1+CD34+ HSPC were found at lower frequency in the blood of T1D patients compared with healthy controls, which was confirmed by measuring mRNA and protein levels. This population of cells was also reduced in the bone marrow of T1D patients. The immunologic basis of this finding appears to be related to an altered micro RNA network relevant for PD-L1 expression, similar to that observed in the NOD mouse model. Last, CD34+ cells from T1D patients were pharmacologically treated to increase PD-L1 expression, and these modulated cells demonstrated an enhanced immunosuppressive effect in vitro.

This novel and informative work may provide an immunologic explanation for the observed therapeutic efficacy of autologous HSPC transplantation in T1D and pave the way for new therapeutic interventions in the future.

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