Epithelial IFNγ signalling and compartmentalized antigen presentation orchestrate gut immunity

Area of Science:

• Immunology
• Cell Biology
• Gastroenterology

Background:

• Epithelial cells express MHC I and IFNγ receptors, but their specific roles in immunity are unclear.
• The function of IFNγ signaling and MHC I antigen presentation in epithelial cells remains unexplored.

Purpose of the Study:

• To investigate the role of epithelial cell-specific IFNγ signaling and antigen presentation.
• To understand how epithelial cells control T cell responses and influence inflammatory diseases.

Main Methods:

• Stimulation of colonic epithelial cells with IFNγ.
• Analysis of antigen presentation to intra-epithelial T cells.
• Assessment of T cell differentiation and inflammasome activation in macrophages.

Main Results:

• IFNγ-sensing colonic epithelial cells present antigens to intra-epithelial T cells.
• Epithelial antigen presentation induces extracellular ATPase in T cells, limiting macrophage NLRP3 inflammasome activation.
• Macrophage-driven antigen presentation promotes pathogenic CD4+ T cell responses, leading to colitis and colorectal cancer.

Conclusions:

• Epithelial cell antigen presentation is a critical checkpoint controlling pathogenic CD4+ T cell responses.
• IFNγ sensing by epithelial cells plays a key role in immune homeostasis at the epithelial barrier.
• Targeting epithelial cell-mediated immunity may offer therapeutic strategies for inflammatory bowel disease and colorectal cancer.