Abstract
CD26 is a T cell activation marker consisting in a type II transmembrane glycoprotein with dipeptidyl peptidase IV (DPPIV) activity in its extracellular domain. It has been described that DPPIV inhibition delays the onset of type 1 diabetes and reverses the disease in non-obese diabetic (NOD) mice. The aim of the present study was to assess the effect of MK626, a DPPIV inhibitor, in type 1 diabetes incidence and in T lymphocyte subsets at central and peripheral compartments. Pre-diabetic NOD mice were treated with MK626. Diabetes incidence, insulitis score, and phenotyping of T lymphocytes in the thymus, spleen and pancreatic lymph nodes were determined after 4 and 6 weeks of treatment, as well as alterations in the expression of genes encoding β-cell autoantigens in the islets. The effect of MK626 was also assessed in two in vitro assays to determine proliferative and immunosuppressive effects. Results show that MK626 treatment reduces type 1 diabetes incidence and after 6 weeks of treatment reduces insulitis. No differences were observed in the percentage of T lymphocyte subsets from central and peripheral compartments between treated and control mice. MK626 increased the expression of CD26 in CD8+ T effector memory (TEM) from spleen and pancreatic lymph nodes and in CD8+ T cells from islet infiltration. CD8+TEM cells showed an increased proliferation rate and cytokine secretion in the presence of MK626. Moreover, the combination of CD8+ TEM cells and MK626 induces an immunosuppressive response. In conclusion, treatment with the DPPIV inhibitor MK626 prevents experimental type 1 diabetes in association to increase expression of CD26 in the CD8+ TEM lymphocyte subset. In vitro assays suggest an immunoregulatory role of CD8+ TEM cells that may be involved in the protection against autoimmunity to β pancreatic islets associated to DPPIV inhibitor treatment.
Highlights
Type 1 diabetes (T1D) results from the progressive destruction of insulin-producing pancreatic β-cells by CD4+ and CD8+ T cells [1]
dipeptidyl peptidase IV (DPPIV) inhibitor MK626 reduces the incidence of diabetes and the insulitis score
The percentage of plasma DPPIV activity was reduced by more than 90% in the MK626-treated group, and this inhibition was maintained throughout the study period, confirming that DPPIV activity was mostly inhibited in the MK626-administered mice (S1A Fig)
Summary
Type 1 diabetes (T1D) results from the progressive destruction of insulin-producing pancreatic β-cells by CD4+ and CD8+ T cells [1]. CD26 is constitutively expressed on the surface of many cell types, including immune cells [3], and a soluble form is present in plasma. It has recently been described that caveolin-1 in antigen presenting cells (APCs) is a binding protein for CD26. Their interaction results in the up-regulation of CD86 in the APC and enhances T cell co-stimulation [9]. The same group demonstrated that the catalytic site of CD26 is located in the pocket structure involved in the caveolin-1 scaffolding domain
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
