Formation of mesenteric tertiary lymphoid organs shapes the immune cell and lymph trafficking from the intestine in a Crohn’s disease-like mouse model

Abstract

Abstract Current understanding of Crohn’s disease (CD) is that hereditary factors render the mucosal surface susceptible by either deregulated interactions between the bacterial flora and surface epithelial cells or an overwhelming host immune response. Given that lymph flow is essential for leukocyte trafficking and lipid absorption, understanding the effects of chronic inflammation in the intestinal-draining lymphatics is crucial for IBD treatment. Proper immune responses in the gut require immune cell migration towards secondary lymphoid organs via mesenteric collecting vessels. Our group described newly developed tertiary lymphoid organs (TLO) in mesenteric fat of CD biopsies, that are formed in association with lymphatic collecting vessels. However, mouse models that resemble lymphatic impairment and TLO formation in IBD are missing. Using a unique IBD model of Crohn’s disease-like ileitis (TNFΔARE mice) we demonstrate that these mice develop mesenteric TLO. Under TNFΔARE background, we generated a lymphatic reporter and a transgenic photoconvertible lines. Our results show that mesenteric TLO are integrated with collecting lymphatic vessels, obstructing leukocyte and lymph traffic from the intestine. Using adoptive transfer of microbiota-dependent TCR Tregs we found that TLO have the capacity to differentiate naïve T cells, yet they harbor tissue-resident T cells, demonstrating their duality. Strikingly, although anti-TNF therapy reduce ileum inflammation, TLO are resistant to the treatment, contributing to TNF therapy relapse or inefficacy. Our results demonstrate that chronic intestinal inflammation extend to the mesentery, impairing immune surveillance of the gut mucosal barrier, altering homeostasis.