title: Aberrant NKG2D expression with IL-17 production of CD4+ T subsets in patients with type 2 diabetes.
abstract: Type 2 diabetes (T2D) is a systemic inflammatory disease. Although the natural killer group 2, member D (NKG2D) receptor, was not expressed normally on CD4+ T cells, the aberrant expression was found in pathological conditions such as in auto-immune diseases. However, the involvement of NKG2D in pathogenesis of T2D is unclear. We hypothesize that there is an inflammatory CD4+ T cell subpopulation expressing NKG2D and producing interleukin (IL)-17 in T2D. NKG2D expression on CD4+ T cells and their subsets were analyzed by multi-color staining using flow cytometry. Lymphocytes were activated by phorbol-12-myristate-13-acetate (PMA) and ionomycin, and were stained for intracellular IL-17. To investigate the mechanism of IL-17 production, patients' lymphocytes were stimulated using specific anti-T cell receptor (TCR) alone, anti-NKG2D alone or a combination of the two antibodies. CD4+ T cells and particularly, CD4+CD28nullT subset of T2D patients were highly expressed NKG2D and more prevalent compared to non-diabetic individuals (ND) (P=0.039 and P=0.022, respectively). Significantly higher percentages of CD4+CD28nullNKG2D+T cells of patients produced IL-17 when compared to those of ND (P=0.024) and were positively correlated with the level of glycated hemoglobin A1c (HbA1c) (R2=0.386, P=0.041). Additionally, this cell population could be stimulated by specific monoclonal anti-NKG2D to produce IL-17. In conclusion, CD4+CD28nullNKG2D+T cells were expanded in T2D, especially in patients with poor glycemic control. NKG2D may be one of the surrogate co-stimulatory receptors leading to irregular inflammatory function producing IL-17. An IL-17 producing CD4+CD28nullNKG2D+T cells may potentially be involved in pathogenesis and drive severity of the disease with the glycemic dependence. This particular cell type could be targeted for prognostic or therapeutic purposes.
authors.affiliation: Biomedical Sciences Program, Graduate School, Khon Kaen University, Khon Kaen 40002, Thailand; The Centre for Research and Development of Medical Diagnostic Laboratories (CMDL), Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen 40002, Thailand. Electronic address: wisitsakphok@gmail.com.
authors.forename: Wisitsak
authors.initials: W
authors.lastname: Phoksawat
authors.affiliation: The Centre for Research and Development of Medical Diagnostic Laboratories (CMDL), Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen 40002, Thailand; Department of Clinical Immunology and Transfusion Sciences, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen 40002, Thailand. Electronic address: jumnainsong@yahoo.com.
authors.forename: Amonrat
authors.initials: A
authors.lastname: Jumnainsong
authors.affiliation: Department of Physiology, and Exercise and Sport Sciences Research and Development Group, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand. Electronic address: naruemon@kku.ac.th.
authors.forename: Naruemon
authors.initials: N
authors.lastname: Leelayuwat
authors.affiliation: The Centre for Research and Development of Medical Diagnostic Laboratories (CMDL), Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen 40002, Thailand; Department of Clinical Immunology and Transfusion Sciences, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen 40002, Thailand. Electronic address: chanvit@kku.ac.th.
authors.forename: Chanvit
authors.initials: C
authors.lastname: Leelayuwat
mesh_terms: D000328:Adult; D000911:Antibodies, Monoclonal; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000276:immunology*; D005260:Female; D015870:Gene Expression; D006442:Glycated Hemoglobin / Q000378:metabolism*; D006801:Humans; D007003:Hypoglycemia; D016130:Immunophenotyping; D020381:Interleukin-17 / Q000378:metabolism*; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000276:immunology / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D006442:Glycated Hemoglobin; D020381:Interleukin-17; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011948:Receptors, Antigen, T-Cell; C527085:KLRK1 protein, human
keywords: CD4+CD28(null)T subset; IL-17; NKG2D; Type 2 diabetes