SLAMF4 is a negative regulator of expansion of cytotoxic intraepithelial CD8+ T cells that maintains homeostasis in the small intestine

Michael S. O'Keeffe, Joo Hye Song, Gongxian Liao, Jaime De Calisto, Peter J. Halibozek, J. Rodrigo Mora, Atul K. Bhan, Ninghai Wang, Hans Christian Reinecker, Cox Terhorst

Research output: Contribution to journalArticle

14 Scopus citations

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 languageEnglish (US)
Pages (from-to)991-1001.e4
JournalGastroenterology
Volume148
Issue number5
DOIs
StatePublished - May 1 2015
Externally publishedYes

Keywords

  • Immune Regulation
  • Immunity
  • Intestinal Epithelium
  • T-Cell Development

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

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    O'Keeffe, M. S., Song, J. H., Liao, G., De Calisto, J., Halibozek, P. J., Mora, J. R., Bhan, A. K., Wang, N., Reinecker, H. C., & Terhorst, C. (2015). SLAMF4 is a negative regulator of expansion of cytotoxic intraepithelial CD8+ T cells that maintains homeostasis in the small intestine. Gastroenterology, 148(5), 991-1001.e4. https://doi.org/10.1053/j.gastro.2015.02.003