Differential Effects of the Absence of Nkx2-3 and MAdCAM-1 on the Distribution of Intestinal Type 3 Innate Lymphoid Cells and Postnatal SILT Formation in Mice

Abstract

Seeding of leukocytes to developing lymphoid tissues in embryonic and early postnatal age and to the mucosa throughout adulthood depends on the interaction between endothelial MAdCAM-1 addressin and its cognate ligand α4β7 integrin. Nkx2-3 as a transcriptional regulator of MAdCAM-1 controls vascular patterning in visceral lymphoid tissues in mice, and has been identified as a susceptibility factor for inflammatory bowel diseases in humans, associated with lymphoid neogenesis in the inflamed intestines. The role of Nkx2-3 in the organogenesis of the solitary intestinal lymphoid tissues (SILTs) involving type 3 innate lymphoid cells (ILC3) is still unknown. Here we investigated the effect of Nkx2-3 on the postnatal distribution of intestinal ILC3s and the development of SILTs, comparing these to mice lacking MAdCAM-1, but preserving Nkx2-3. At 1 week of age small intestines (SI) contained significantly higher number of ILC3s relative to the colon, with a substantial reduction in MAdCAM-1−/− mice compared to C57BL/6 controls. One week later SI ILC3 number decreased in all genotypes, the number of colonic ILC3 of both Nkx2-3-deficient and Nkx2-3-heterozygous mice significantly increased. On the fourth postnatal week a further reduction of SI ILC3s was observed in both Nkx2-3-deficient and Nkx2-3-heterozygous mice, while in the colon the number of ILC3s showed a significant reduction in all genotypes. At 1 week of age only sporadic SILT components were present in all genotypes. By the second week mice deficient for either Nkx2-3 or MAdCAM-1 showed absence of SILT maturation compared to their relevant controls, lacking mature isolated lymphoid follicles (ILF). By the fourth week both Nkx2-3-deficient and Nkx2-3-heterozygous mice showed a similar distribution of ILFs relative to cryptopatches (CP), whereas in MAdCAM-1−/− mice CPs and immature ILFs were present, mature ILFs were scarce. Our data demonstrate that the complete absence of MAdCAM-1 partially impairs intestinal seeding of ILC3s and causes partial blockade of SILT maturation, without affecting peripheral lymph node development. In contrast, the inactivation of Nkx2-3 permits postnatal seeding, and its blocking effect on SILT maturation prevails at later stage, thus other adhesion molecules may compensate for the intestinal homing of ILC3s in the absence of MAdCAM-1.

Splenectomy modulates the immune response but does not prevent joint inflammation in a mouse model of RA

“…In our previous study, we investigated the effect of the Nkx2-3 transcription factor (TF) genetic deficiency in autoimmune arthritis [ 26 ]. Nkx2-3 is a homeodomain TF which is crucial for the development of the spleen, and the expression and regulation of mucosal addressin cell adhesion molecule-1 (MADCAM-1) [ 28 , 29 ]. Nkx2-3 deficient mice (Nkx2-3 −/− ) hence have a severely disturbed spleen structure with the lack of the marginal zone and the red pulp, and thus they are incapable of providing the necessary microenvironment for B-cell maturation and T-cell-dependent (TD) immune reactions [ 30 ].…”

Development and Validation of an Autophagy-Related Signature for Head and Neck Squamous Cell Carcinoma

“…NKX2-3 plays crucial roles in many biologic processes, including cell proliferation and growth, metabolic process, immune and inflammatory response, and angiogenesis [ 29 , 30 ]. However, the abnormal expression of NKX2-3 is mostly seen in digestive system diseases, which has been considered as a gene related to inflammatory bowel disease and Crohn's disease [ 31 , 32 ]. A study has found that NKX2-3 could regulate the Wnt signaling pathway and then play a critical role in the pathogenesis of colorectal cancer and could be a new biomarker for clinical practice, including early diagnosis and subsequent therapy [ 33 , 34 ].…”

Quantitative Analysis of NKX2-3 Expression in Human Colon: An Immunohistochemical Study

“…21,22 As an important regulator, Nkx2-1 has been identified to influence rearranged during transfection (RET) expression in enteric neural cells, 23 whereas Nkx2-3 acts as a critical mediator promoting intestinal vascular patterning, [24][25][26] also influencing PP high-endothelial-venule (HEV) vascular addressin specification and gut lymphocyte homeostasis. 27,28 Lack of Nkx2-3 confers protection from colitis in a chemically induced mouse model. 29 Furthermore, Nkx2-3 + pericryptal mesenchymal cells may also contribute to the colonic epithelial stem cell niche, potentially influencing colonic cancer progression.…”