Abstract
Background & Aims Intraepithelial T lymphocyte cells (IEL) are the first immune cells to respond to pathogens; they help maintain the integrity of the epithelial barrier. We studied the function of the mouse glycoprotein Signaling Lymphocyte Activation Molecule Family receptor (SLAMF) 4 (encoded by Slamf4) on the surface of CD8αβ αβ T-cell receptor (TCR)+ IELs, and the roles of these cells in homeostasis of the small intestine in mice. Methods SLAMF4- CD8+ αβTCR+ cells isolated from spleens of OT-I Rag1-/- mice were induced to express gut-homing receptors and transferred to C57BL/6J mice; levels of SLAMF4+ cells were measured in small intestine tissues. After administration of anti-CD3 or antigen, with or without anti-SLAM4, to C57BL/6J and Slamf4-/- mice, CD8αβ αβTCR+ IELs were collected; cytokine production and cytotoxicity were measured. Depletion of CX3CR1+ phagocytes was assessed in mice by live-cell confocal imaging or by cytofluorometry; small intestine tissues were analyzed by histology and inflammation was quantified. Results Splenic CD8+ αβTCR+ cells began to express SLAMF4 only after migrating to the small intestine. Injection of C57BL/6J mice with anti-SLAMF4 and anti-CD3 increased levels of interleukin 10 and interferon gamma secretion by IEL, compared with injection of anti-CD3 only. Similarly, the number of granzyme B+ cytotoxic CD8+ αβTCR+ IELs increased in Slamf4-/- mice after injection of anti-CD3 and anti-SLAMF4, administration of antigen, or injection of anti-CD3. Surprisingly, in vivo activation of CD8αβ+ IELs with anti-CD3 or antigen caused transient depletion of CX3CR1+ phagocytes, which was prolonged by co-injection with anti-SLAMF4 or in Slamf4-/- mice. Anti-CD3 aggravated inflammation in the small intestines of Slamf4-/- mice and Eat2a-/- Eat2b-/- mice, indicated by flattened villi and crypt hyperplasia. Conclusions In mice, the intestinal environment induces SLAMF4 expression and localization to the surface of CD8+ αβTCR+ IELs. Signaling via SLAMF4 controls expansion of cytotoxic CD8αβ+ IELs, which regulate the reversible depletion of lamina propria phagocytes and inflammation in the small intestine.
Original language | English (US) |
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Pages (from-to) | 991-1001.e4 |
Journal | Gastroenterology |
Volume | 148 |
Issue number | 5 |
DOIs | |
State | Published - May 1 2015 |
Externally published | Yes |
Keywords
- Immune Regulation
- Immunity
- Intestinal Epithelium
- T-Cell Development
ASJC Scopus subject areas
- Hepatology
- Gastroenterology