Human colonic myofibroblasts promote expansion of CD4⁺ CD25 ^high Foxp3⁺ regulatory T cells

Background & Aims: Regulatory T (T_reg) cells (CD4 ⁺ CD25^high FoxP3⁺) regulate mucosal tolerance; their adoptive transfer prevents or reduces symptoms of colitis in mouse models of inflammatory bowel disease. Colonic CD90⁺ mesenchymal myofibroblasts and fibroblasts (CMFs) are abundant, nonprofessional antigen-presenting cells in the normal human colonic mucosa that suppress proliferation of activated CD4⁺ effector T cells. We studied CMF suppressive capacity and evaluated the ability of CMF to induce T_reg cells. Methods: Allogeneic cocultures of CD4⁺ T cells and CMFs, derived from normal mucosa of patients undergoing colectomy for colon cancer or inflamed colonic tissues from patients with ulcerative colitis or Crohn's disease, were used to assess activation of the T_reg cells. Results: Coculture of normal CMF with resting or nave CD4⁺ T cells led to development of cells with a T_reg phenotype; it also induced proliferation of a CD25⁺ CD127^- FoxP3⁺ T cells, which expressed CTLA-4, interleukin-10, and transforming growth factorβ and had suppressive activities. In contrast to dendritic cells, normal CMFs required exogenous interleukin-2 to induce proliferation of naturally occurring T_reg cells. Induction of T_reg cells by normal CMFs required major histocompatibility complex class II and prostaglandin E ₂. CMFs from patients with inflammatory bowel diseases had reduced capacity to induce active T_reg cells and increased capacity to transiently generate CD4⁺CD25^+/- CD127⁺ T cells that express low levels of FoxP3. Conclusions: CMFs suppress the immune response in normal colon tissue and might therefore help maintain colonic mucosal tolerance. Alterations in CMF-mediated induction of T_reg cells might promote pathogenesis of inflammatory bowel diseases.