Loss of Peripheral Protection in Pancreatic Islets by Proteolysis-Driven Impairment of VTCN1 (B7-H4) Presentation Is Associated with the Development of Autoimmune Diabetes

Abstract

Antigen-specific activation of T cells is an essential process in the control of effector immune responses. Defects in T cell activation, particularly in the co-stimulation step, have been associated with many autoimmune conditions including type 1 diabetes (T1D). Recently, we demonstrated that the phenotype of impaired negative co-stimulation, due to reduced levels of V-set domain-containing T cell activation inhibitor-1 (VTCN1) protein on antigen-presenting cells, is shared between diabetes-susceptible NOD mice and human T1D patients. Here, we show that a similar process takes place in the target organ, as both α and β cells within pancreatic islets gradually lose their VTCN1 protein during autoimmune diabetes development despite the up-regulation of the VTCN1 gene. Diminishment of functional islet cells' VTCN1 is caused by the active proteolysis by metalloproteinase NRD1 and leads to the significant induction of proliferation and cytokine production by diabetogenic T cells. Inhibition of NRD1 activity, on the other hand, stabilizes VTCN1 and dulls the anti-islet T cell responses. Therefore, we suggest a general endogenous mechanism of defective VTCN1 negative co-stimulation, which affects both lymphoid and peripheral target tissues during T1D progression and results in aggressive anti-islet T cell responses. This mechanism is tied to up-regulation of NRD1 expression and likely acts in two synergistic proteolytic modes: cell-intrinsic intracellular and cell-extrinsic systemic. Our results highlight an importance of VTCN1 stabilization on cell surfaces for the restoration of altered balance of immune control during T1D.

Potential targeting of B7‐H4 for the treatment of cancer

“…In doing so, the median survival of the B7‐H4 high patients was only 42.2 months, as compared to 106.9 months for the B7‐H4 low patient population . Similar to the previously mentioned study assessing changes in systemic levels of soluble B7‐H4 in aging NOD mice, the level of soluble B7‐H4 present within the sera of patients with renal cell carcinoma and gastric cancer has been reported to correlate with disease severity. Serum levels of soluble B7‐H4 in gastric cancer patients were significantly higher than those of healthy control volunteers.…”

“…The majority of the research regarding B7‐H4 has focused the functional consequence of B7‐H4 interaction with the putative B7‐H4R on the B7‐H4R‐expressing cell, several papers indicate distinct intracellular effects such as decreased apoptosis, enhanced proliferation, and facilitated metastasis in B7‐H4‐expressing cells themselves. Besides the level of cell surface expressed B7‐H4, studies assessing the level of soluble B7‐H4 in serum have shown B7‐H4 to be a putative biomarker for the level of disease . This, however, may be a potential confounder with the use of B7‐H4‐binding reagents, as B7‐H4‐binding reagents, i.e.…”

“…In NOD mice, the loss pancreatic islet cell expressed B7‐H4 may either be a genetically induced phenotype or this alteration in the level of surface B7‐H4 may be induced by inflammatory immune cells infiltrating into the pancreatic islets. The loss of B7‐H4 from the pancreatic islet cells did not appear to be solely due to the presence of inflammatory immune cells, as determined by the transfer of splenocytes from diabetic NOD mice into B6 g7 mice . Therefore, it was concluded that a genetic difference between strains of mice may be responsible for this alteration in NRD1‐induced cleavage of B7‐H4 from the surface of pancreatic islet cells.…”

“…The loss of B7-H4 from the pancreatic islet cells did not appear to be solely due to the presence of inflammatory immune cells, as determined by the transfer of splenocytes from diabetic NOD mice into B6 g7 mice. 43 Therefore, it was concluded that a genetic difference between strains of mice may be responsible for this alteration in NRD1-induced cleavage of B7-H4 from the surface of pancreatic islet cells. Taken together, the expression of B7-H4 cell surface protein appears to be activation induced and may represent an immune mechanism by which immune homeostasis can be induced within sites of inflammation.…”

“…In doing so, the median survival of the B7-H4 high patients was only 42.2 months, as compared to 106.9 months for the B7-H4 low patient population. 65 Similar to the previously mentioned study assessing changes in systemic levels of soluble B7-H4 in aging NOD mice, 43 trigger macrophages to secrete IL-6 and IL-10, and IL-6 and IL-10 in turn stimulate APCs to express B7-H4. 60 In human lung cancer, tumorassociated macrophages were shown to produce IL-10, TNFα, and a small amount of IFNγ, that can also induce human lung cancer cells to express B7-H4.…”