Gut autoimmunity provoked by loss of goblet-cell mimetics in the thymus

Autoimmune diseases, including many Inflammatory Bowel Diseases (IBD), reflect a breakdown in immunological tolerance. The immune system is designed to respond to foreign molecules (nonself-antigens) while ignoring an organism’s own constituents (self-antigens). For T cells, much of this self-tolerance is learned during their maturation in the thymus, through either elimination of potentially self-reactive cells or their pacification. But how is the T-cell repertoire purged of cells that recognize antigens not encountered until after they migrate into the periphery? We recently discovered a novel mechanism for previewing peripheral antigens to maturing T cells: thymic mimetics. These amazing cells are molecular hybrids between a small group of thymic stromal cells and diverse peripheral cell-types, and were shown to promote immunological tolerance to the peripheral cell-types’ antigens. A mimetic cell-type that has drawn our attention is thymic goblet-cell mimetics. Goblet cells, prominent in the intestine, safeguard the organism from microbial invasion by secreting mucins to form a protective mucus layer. Individuals with IBD often have aberrant goblet-cell histology and/or anti-goblet-cell autoantibodies. The overall goals of this project are to determine whether and how thymic goblet-cell mimetics control intestinal self-reactivity in mice and whether at least some human IBDs have a similar etiology.