The Ig-like glycoprotein CD101 amplifies anti-bacterial properties of phagocytes

Introduction

T lymphocytes and myeloid cells express CD101, an Ig-like glycoprotein, predominantly in the gut. While CD101-expressing T lymphocytes ameliorate the severity of DSS- and T cell transfer-induced colitis and sustain the function of regulatory T cells, the biology of CD101 on myeloid cell subsets is less well understood.

Goals

Therefore we investigated the myeloid cell-specific functions of CD101 in oral and systemic Salmonella infection models.

Materials & Methods

We assessed the regulation of CD101 expression, the composition of intestinal microbiota, the intraluminal metabolome, Salmonella replication and the severity of intestinal inflammation in mouse models of acute and chronic Salmonella-induced colitis using conditional CD101-knockout mice crossed to CD11c Cre, LyzM Cre and Cx3Cr1 Cre mice as well as in patients suffering from inflammatory bowel disease (IBD).

Results

Neutrophil specific conditional CD101 KO mice harbored less neutrophils in the bone marrow, like conventional CD101 KO mice and exhibited distinct variations in the composition of intestinal microbiota following Salmonella infection. CD101-expressing neutrophils, but not other CD101-expressing myeloid cell subsets restrained Salmonella infection in vitro and in vivo. CD101-intrinsic and -extrinsic mechanisms contributed to the control of bacterial replication and systemic spread, and the CD101-dependent containment of Salmonella infection depended on the concomitant expression of Irg-1 and Nox2 along with an increased accumulation of itaconate and reactive oxygen species in neutrophils. An increased circulation of intestinal microbial antigens in the sera of IBD patients correlated inversely with the distribution of CD101 expression on myeloid cells, mirroring the suppression of CD101 in mice following Salmonella infection.

Summary

When expressed on neutrophils, CD101 restrains infection due to the control of metabolic, immune-regulatory and anti-microbial processes. To what extent CD101 shapes the composition of intestinal microbiota and how CD101-dependent microbiota promotes colonization resistance to Salmonella infection, is subject of further investigation.