PD-1, CTLA-4, LAG-3, and TIGIT: The roles of immune checkpoint receptors on the regulation of human NK cell phenotype and functions.

The roles of immune checkpoint receptors were defined in many cancers and autoimmune diseases, while there is limited information on their functional roles in the NK cells of healthy individuals. Immune checkpoint receptor expression of NK cell subsets and their association with NK cell functions (cytotoxic capacity and cytokine production) in healthy population were investigated. PD-1, CTLA-4, LAG-3 and TIGIT expression of peripheral blood NK cells, cytokine levels (TNF-alpha, IFN-gamma, IL-10) and cytotoxic functions (granzyme A, perforin, CD107a; with/without K562 target cell stimulation) were evaluated by flow cytometry. CD56(dim)CD16(dim) NK cells had the highest expression of TIGIT, while CD56(dim)CD16 NK cells had highest expression of PD-1, CTLA-4 and LAG-3. PD-1(+) NK cells, CTLA-4(+) NK cells and LAG-3(+) NK cells had increased amount of IL-10 however, reduced IFN-gamma and TNF-alpha levels. Cytotoxic granule expressions (perforin and granzyme A) were reduced in PD-1(+) NK cells, CTLA-4(+) NK cells and LAG-3+ NK cells. However, TIGIT expression did not alter perforin and granzyme A expressions. Degranulation capacity was reduced in three groups of NK cells (PD-1(+) or LAG-3(+) or TIGIT(+)). TIGIT(+) NK cells responded strongly to target cell stimulation, while NK cells in the other groups (PD-1(+) or CTLA-4(+) or LAG-3(+)) were resistant. PD-1(+) NK cells, CTLA-4(+) NK cells and LAG-3(+) NK cells had a regulatory phenotype, impaired cytotoxic functions, and response to target cell stimulation. In contrast, TIGIT(+) NK cells had strong baseline cytotoxic activity that further increased in response to target cell stimulation

IL-22-secreting Th22 and IFN-gamma-secreting Th17 cells in Behcet's disease

Objective. Behcet's disease (BD) is a systemic inflammatory disease with unknown etiology. Studies have shown that some T helper (Th) 1-associated cytokines have role in the inflammation of BD. The CD4(+) Th cells can be differentiated into Th1, Th2, Th17 and Th22 secrete different cytokines to regulate immune system. In this study, cytokine secretion of Th subsets in BD was investigated

Natural Killer Cell Subsets and Their Functional Activity in Behcet's Disease

Background: Behcet's disease (BD) is a rare, chronic autoinflammatory disorder of unknown origin. Natural killer (NK) cells are one of the major immunoregulatory cell groups of the innate immune system, but their role in BD pathogenesis is not well documented.Objectives: We aimed to investigate the role of NK cell subsets and their cytokine secretion and cytotoxic activity in patients with BD.Patients and methods: The study group consisted of BD patients who had only mucocutaneous involvement, and they were compared with healthy subjects. BD patients were divided into two groups according to their frequencies of oral ulcerations. NK cell cytotoxicity was determined using CD107a expression and a CFSE-based cytotoxicity test. Expression of NK cell receptors and surface markers and the intracellular IL-5, IL-10, IL-17, and IFN- levels in CD16(+) NK cells were assessed by flow cytometry.Results: Although the cytokine secretion pattern was different, no difference was obtained in cytotoxic activity, expression of activatory receptors, or degranulation of NK cells.Conclusion: Increases in NK1/NK2 ratio and CD16(+)IFN-(+) NK1 cells might support the idea of a biased IFN- dominant immune response in the mucocutaneous involvement of BD pathogenesis. Although the cytokine secretion pattern was different, no difference was obtained in cytotoxic activity, expression of activatory receptors, or degranulation of NK cells

Plasma concentrations of soluble cytokine receptors in euthymic bipolar patients with and without subsyndromal symptoms

BACKGROUND: Current evidence suggests that high concentrations of pro-inflammatory markers are associated with bipolar disorder characterized by severe impairment during inter-episodic periods, reduced treatment response and persistent subsyndromal symptoms. We tested whether persistent subsyndromal symptoms in euthymic bipolar patients were associated with markers of an ongoing chronic pro-inflammatory process. METHODS: Forty-five euthymic bipolar patients (22 with subsyndromal symptoms (BD+) and 23 without subsyndromal symptoms (BD-) and 23 well controls (WC) were recruited for assessment of soluble tumor necrosis factor receptor-1 (sTNF-R1), soluble interleukin-6 receptor (sIL-6R) and soluble interleukin-2 receptor (sIL-2R) concentrations. Soluble cytokine receptor concentrations were assessed using enzyme-linked immunosorbent assay. RESULTS: In comparison to WC, sTNF-R1 concentration was higher in both BD- and BD+ (age and sex adjusted standardized β, respectively: β = 0.34, p = 0.012 and β = 0.41, p = 0.003). Similarly, compared to WC, sIL-6R concentration was higher in both BD- and BD+ (age and sex adjusted standardized β, respectively: β = 0.44, p = 0.001 and β = 0.37, p = 0.008). There was no difference between BD- and BD+ in the concentration of either sTNF-R1 or sIL-6R; plasma concentration of sIL-2R was not analyzed as 75% percent of the samples were non-detectable. CONCLUSIONS: Although bipolar patients present with a pro-inflammatory shift compared to well controls, subsyndromal symptoms are not associated with additive increasing effects. Longitudinal studies with larger samples are required to clarify the relationship between illness course and inflammatory markers in bipolar disorder