Unique invariant natural killer T cells promote intestinal polyps by suppressing TH1 immunity and promoting regulatory T cells

Abstract

CD1d-restricted invariant natural killer T (iNKT) cells are known as potent early regulatory cells of immune responses. Besides the established roles in the regulation of inflammation and autoimmune disease, studies have shown that iNKT cells have important roles in tumor surveillance and the control of tumor metastasis. Here we found that absence of iNKT cells dramatically decreased the total number of intestinal polyps in APCMin/+ mice, a model for colorectal cancer. Polyp iNKT cells were enriched for IL-10 and IL-17 producing cells, showed a distinct phenotype being CD4+, NK1.1− CD44int and PD-1lo, and they were negative for the NKT cell transcription factor PLZF. Absence of iNKT cells was associated with a reduced frequency of Treg cells and lower expression levels of FoxP3 protein and transcript uniquely in the polyps, and a switch to an inflammatory macrophage phenotype. Moreover, in iNKT cell deficient APCMin/+ mice, expression of T helper (TH) 1-associated genes, such as IFN-γ and Nos2, was increased in polyps, concomitantly with elevated frequencies of conventional CD4+ and CD8+ T cells in this tissue. The results suggest that a population of regulatory iNKT cells locally promote intestinal polyp formation by enhancing Treg cells and immunosuppression of anti-tumor TH1-immunity.

NKT cells and the regulation of intestinal immunity: a two‐way street

“…Consistent with this, NKT cells are the major producers of IL‐4 in this tissue, and after stimulation of mLN lymphocytes with PMA/ionomycin, iNKT cells constitute up to 60% of the IL‐4‐producing cells . Finally, NKT10 cells are also found in the intestine of transgenic mouse models of colorectal cancer (APC Min/+ mice) . It is worth noting that while the majority of iNKT cells found in the adult murine gut in steady state are T‐bet + NKT1s, it is possible that other iNKT cell subsets (or precursors) could be recruited/expanded under certain inflammatory conditions ultimately shaping the functional capabilities of the local iNKT cell population.…”

“…In C57Bl/6 mice, NKT1 cells are highly abundant and especially enriched in liver, spleen and thymus, NKT2 cells are abundant in mesenteric lymph node (mLN), and NKT17 cells are enriched in lungs as well as in inguinal (iLN), axillary (aLN) and cervical (cLN) LNs . NKT10 cells preferentially accumulate in adipose tissue in homeostasis, but can be induced in response to immunisation and are found in the intestine of transgenic mouse models of colorectal cancer (APC Min/+ mice) . On the other hand, NKT FH and NKTregs have been only detected in mice during immune responses .…”

“…As such, Treg numbers and frequencies are altered in the mLN and SI of CD1d‐KO mice vs. littermate controls, while activation of iNKT cells in response to oral αGalCer results in increased numbers of peripherally induced Tregs . Moreover, a population of regulatory iNKT cells in the intestine has been shown to locally promote intestinal polyp formation by enhancing Treg cell frequency in a mouse model of colorectal cancer . Finally, CD1d‐mediated NKT cell–APC interactions can also modulate APC activation and function and ultimately shape intestinal immunity.…”

Eicosapentaenoic acid and/or aspirin for preventing colorectal adenomas during colonoscopic surveillance in the NHS Bowel Cancer Screening Programme: the seAFOod RCT

“…158 The tumour immunology of the colorectal adenoma has been largely ignored, perhaps because of the relative difficulty in collecting sufficient, fresh human colorectal adenoma tissue and absence of a suitable animal model. 159 However, regulation of host immune surveillance as a mechanism of primary CRC chemoprevention activity remains a valid hypothesis for both seAFOod trial interventions. 160 We have recently reported that mixed ω-3 PUFA treatment is associated with an increase in abundance of SCFA-producing bacteria in the colon.…”

YY1lo NKT cells are dedicated IL-10 producers

“…For example, control of homeostasis in the visceral adipose tissue is dependent on IL-10 from NKT cells 14 , as are some aspects of cardiac remodeling 15 . Autoimmune diseases ranging from alopecia areata 16 to insulin-dependent diabetes mellitus 17 are associated with IL-10 producing NKT cells 18,19 , as is the growth of intestinal polyps that can lead to cancer 20 .…”