Reduced γδ intraepithelial lymphocyte number and motility precede the onset of Crohn’s disease-like ileitis
Year: 2023
Type: conference-abstract
Abstract: Crohn’s disease (CD) is a relapsing, remitting disease resulting in chronic intestinal inflammation. Recent studies of resected ileal tissue from CD patients reported a loss of intraepithelial lymphocytes expressing the γδ T cell receptor (γδ IELs). γδ IELs continuously survey the epithelial barrier and protect against experimental colitis; however, the role of γδ IELs in the initiation of ileitis is unknown. To this end, we profiled the IEL compartment in TNFΔARE/+ mice, which develop chronic CD-like ileitis at 8 wks old, prior to and during ileitis onset (4–10 wks). We observed a 2.5-fold reduction in the frequency of ileal γδ IELs in 5-wk-old TNFΔARE/+ mice compared to TNF+/+ (WT) littermates (p<0.001). Using intravital microscopy, we observed reduced γδ IEL surveillance behavior (10.6 vs 6.4 mm/min track speed mean, p<0.0001) in TNFΔARE/+ mice compared to WT at 6 wks. Analysis of cleared ileal tissue from 6-wk-old WT and TNFΔARE/+ mice revealed a reduction in the number of γδ IELs in villus tips in TNFΔARE/+ mice relative to WT, thereby increasing the proportion of γδ IELs found in the crypt region. Based on several reported links between γδ IELs and Paneth cells (PC), we quantified PCs by lysozyme immunostaining in ileal tissue. We found an increased proportion of morphologically abnormal PCs in 6-wk-old TNFΔARE/+ mice, reflecting PC dysfunction consistent with CD pathology. These findings are supported by a reduction in ileal Lyz1 expression in TNFΔARE/+ mice compared to WT prior to ileitis onset (p=0.02). Together, these studies demonstrate that γδ IELs exhibit impaired surveillance behavior and altered distribution along the crypt/villus axis prior to ileitis onset, which coincides with PC dysfunction in CD-like ileitis. COCR23PRF017 NJCCR Predoctoral Fellowship Golovchenko (PI) June 1, 2022 – May 31, 2024 γδ IEL surveillance behavior in the onset of chronic ileitis
Source: The Journal of Immunology
Authors: Natasha B Golovchenko, Weili Xu, Andrew Fong, Lanjing Zhang, Karen Edelblum
Language: English
Topic: Inflammatory Bowel Disease
Subfield: Genetics
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W4385686240