Novel antigen-presenting cell imparts T_reg-dependent tolerance to gut microbiota

Area of Science:

• Immunology
• Cell Biology
• Developmental Biology

Background:

• Establishing immune tolerance is vital for health, preventing autoimmune reactions and responses to harmless antigens.
• Medullary thymic epithelial cells (mTECs) expressing autoimmune regulator (AIRE) are key for central tolerance in the thymus.
• Peripheral regulatory T (Treg) cell differentiation occurs early in life upon exposure to dietary and microbial antigens, but the responsible cells were unknown.

Purpose of the Study:

• To identify the specific antigen-presenting cells responsible for generating peripheral regulatory T (pTreg) cells during a critical early-life window.
• To characterize the unique features and developmental origins of these pTreg-inducing cells.
• To elucidate the mechanisms by which these cells establish immune tolerance in the gut.

Main Methods:

• Identification and characterization of a novel RORγt+ antigen-presenting cell population, termed Thetis cells, in intestinal lymph nodes.
• Transcriptional profiling and sub-grouping of Thetis cells (TC I-IV).
• Genetic manipulation to assess the role of Major Histocompatibility Complex class II (MHCII) and integrin αvβ8 (ITGB8) in Thetis cell function and pTreg differentiation.

Main Results:

• Thetis cells, a novel class of RORγt+ antigen-presenting cells with mTEC and dendritic cell features, were identified.
• A specific sub-group, TC IV, lacked AIRE but expressed molecules like αvβ8 crucial for pTreg generation.
• Thetis cell-specific loss of MHCII or ITGB8 severely impaired intestinal pTreg differentiation, leading to colitis, highlighting TC IV's essential role.

Conclusions:

• Thetis cells, particularly the TC IV subset, are the primary RORγt+ antigen-presenting cells responsible for inducing peripheral Treg cells in early life.
• These findings reveal parallel pathways for immune tolerance in the thymus and periphery, involving shared cellular and transcriptional programs.
• Thetis cells are critical for maintaining intestinal homeostasis and preventing inflammatory diseases like colitis.