Regulatory iNKT cells lack expression of the transcription factor PLZF and control the homeostasis of Treg cells and macrophages in adipose tissue

Abstract

iNKT cells are CD1d-restricted lipid-sensing innate T cells that express the transcription factor PLZF. iNKT cells accumulate in adipose tissue, where they are anti-inflammatory, but the factors that contribute to their anti-inflammatory nature, and their targets in adipose tissue are unknown. Here we report that adipose tissue iNKT cells have a unique transcriptional program and produce interleukin 2 (IL-2) and IL-10. Unlike other iNKT cells, they lack PLZF, but express the transcription factor E4BP4, which controls their IL-10 production. Adipose iNKT cells are a tissue resident population that induces an anti-inflammatory phenotype in macrophages and, through production of IL-2, controls the number, proliferation and suppressor function of adipose regulatory T (Treg) cells. Thus, adipose tissue iNKT cells are unique regulators of immune homeostasis in this tissue.

Activation and Function of iNKT and MAIT Cells

“…Interestingly, there were found to be many Vβ rearrangements in the iNKT cells of an individual mouse, with little overlap when individual mice were compared, or even individual organs within a mouse. This is indicative of the small size for any iNKT cell clone Ronet et al, 2001) and is also consistent with the finding that iNKT cells in lung, liver, adipose tissue, and other sites tend not to recirculate (Lynch et al, 2015;Scanlon et al, 2011;Thomas et al, 2011). In contrast, in human MAIT cells, there were oligoclonal expansions, as evidenced by repeated TCR CDR3β sequences (Dusseaux et al, 2010;Tilloy et al, 1999).…”

Cross-talk between iNKT cells and monocytes triggers an atheroprotective immune response in SLE patients with asymptomatic plaque

“…This suggests that iNKT cell-monocyte/macrophage cross-talk and the promotion of M2 macrophage differentiation is a more complex mechanism potentially involving other cytokines including IL-13, which was increased in response to F5 lipid stimulation (Fig. 3E), and transactivation of other cell types (18,44). Conversely, during the later stages of atherosclerosis (in SLE-CV patients and in SLE-P patients with 3-4 plaque sites), this protective response appeared to be reduced or overwhelmed leading to iNKT cell exhaustion, reduced anti-inflammatory M2-like monocytes and increased pro-inflammatory 'intermediate' monocyte populations, in line with studies showing a predominance of M1 macrophages in more advanced rupture prone lesions (46)(47)(48) where the immune balance shifts from tissue repair towards chronic inflammation.…”

From the Deep Sea to Everywhere: Environmental Antigens for iNKT Cells

“…Another point to consider is that the observation that mice without bacterial commensals in the first weeks of life have more iNKT cells in the mucosa does not in itself imply that iNKT cells are responding differently before and after this time cut-off. It is well established that once they migrated into the peripheral tissue, iNKT cells hardly migrate any longer and remain tissue resident (Lynch et al 2015;Thomas et al 2011). This would suggest that once iNKT cells migrate into the mucosa, they remain there irrespective of the presence of commensals.…”

“…Following TCR stimulation, they rapidly produce copious amounts of various cytokines including Th1 cytokines, like IFN-c and tumor necrosis factor; Th2 cytokines, like IL-4 and IL-13; and Th17 cytokines (Bendelac et al 2007;Brennan et al 2013;Kronenberg 2005;Salio et al 2014;Wingender and Kronenberg 2008). Furthermore, iNKT cell subsets specialized in T follicular helper-like functions (Chang et al 2011a;King et al 2011;Tonti et al 2012) or IL-10 dependent regulatory functions (Lynch et al 2015;Sag et al 2014) have been described. This rapid production of cytokines is more similar to innate immune cells or to memory T cell response, as naïve conventional T cells would take days of stimulation to produce these cytokines.…”