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    • In mice iNKT cells are most frequent

    2022-01-10

    In mice, iNKT cells are most frequent (20–30%) among liver T lymphocytes, while they only constitute 0.4–1% of the total T cells in thymus, bone marrow, spleen, lymph node, and intraepithelial lymphocytes. In humans, iNKT cells constitute approximately only a 0.1–0.2% of the peripheral blood T lymphocytes, and iNKT cells are present in the spleen, liver, thymus, bone marrow, and peripheral lymph nodes [12].iNKT cells recognize, through their semi-invariant TCR, glycolipid antigens, such as α-galactosylceramide (α-GalCer) and its analogs, presented by antigen presenting cells (APC) in the context of CD1d presenting molecules [13]. After TCR ligation, iNKT cells promptly produce a large amount of the T helper (Th)1 and Th2 cytokines [e.g., interferon (IFN)-γ and interleukin (IL)-4] [12]. The cytokine burst from activated iNKT cells triggers DC maturation, NK cell proliferation, and expression of B cell activation markers, these events together contributing to adaptive immune responses. On the other hand, iNKT cells display important cytotoxic activities, which are essential for immune responses [14]. Recently, evidences on the role of environmental factors, such as histamine [15], IL-33 [16], and prostaglandin D2 [17], as well as of costimulatory molecules (e.g., CD80/86–CD28, and CD154–CD40) [13], in specifically activating iNKT cells have been reported. Our group [18] showed that the culture medium from human monocytic cell lines (THP-1), expressing the kynurenine pathway and releasing micromolar concentrations of l-kynurenine and KYNA following α-GalCer stimulation, is able to stimulate mouse iNKT hybridoma cells to release IL-2. These data suggested the possibility that iNKT cells express specific surface receptors for the kynurenines.
    Materials and methods
    Results
    Discussion A large bulk of literature data demonstrates the biology of the CD1d system [24], the structure of glycolipid 3X FLAG Peptide [25], and the role of iNKT cells in suppressing or enhancing immune-mediated diseases [26]. The underlying basis for these diverse functions of iNKT cells is, however, still unclear. The existence of distinct iNKT cell subsets [27], as well as of different tissue-specific microenvironments (cytokines and/or costimulatory signals) [28] and receptors (e.g., histamine receptor H4 and prostaglandin D2 receptor) [15], [17] have been proposed as key factors. Here, we add another un-known possibility that is GPR35, which is expressed in human iNKT cells (Fig. 1). The selective activation of this receptor by KYNA or zaprinast induced a significant reduction in IL-4 secretion from human iNKT cells, while preserving the production of IFN-γ (Fig. 3A and B). The mechanisms mediating these immunomodulatory effects are still un-known. It might be possible that following GPR35 activation the synthesis and/or the binding activity of some IL-4 transcription factors (e.g., GATA-3 [29], NFAT2 [30] and AP-1 [31]) is decreased, and we are trying to clarify this point. From present results, the level of GPR35 expression in human iNKT cells is lower than in resting PBMC. This observation is consistent with that previously reported by Wang et al. [6] in human peripheral leukocytes. These Authors also showed that GPR35 activation induces the receptor translocation from plasma membrane to intracellular structures in a GPR35-transfected tumor cell line. Here we have confirmed these results in human iNKT cells. An intriguing question is how and when GPR35 activation can contribute to the modulation of iNKT cell functions. The concentrations of KYNA in human plasma of healthy volunteers range 30–50nM [32], a range which is well below the concentrations (300μM) we have determined to be effective in stimulating GPR35 in human iNKT cells. However, the experimental cells we have used originated from selective expansion of PBMC by α-GalCer treatment for 14days and it is well known that this procedure may have functional consequences. The response of iNKT cells to repetitive α-GalCer treatment is, indeed, characterized by a dramatic down-regulation of their TCR and NK1.1 surface receptors [33]. As for conventional T cells [34], the down-regulation of iNKT TCR results from decreased surface recycling of internalized receptor and implies the need for high antigen levels for stimulating cell responses. Similarly, GPR35 might be down-regulated in human iNKT cells under our experimental conditions and this could explain the low potency of KYNA and zaprinast we have measured in inducing receptor-mediated responses.