Gastroenterology

Gastroenterology

Volume 140, Issue 7, June 2011, Pages 2019-2030
Gastroenterology

Basic—Alimentary Tract
Human Colonic Myofibroblasts Promote Expansion of CD4+ CD25high Foxp3+ Regulatory T Cells

https://doi.org/10.1053/j.gastro.2011.02.059Get rights and content

Background & Aims

Regulatory T (Treg) cells (CD4+ CD25high 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 Treg 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 Treg cells.

Results

Coculture of normal CMF with resting or naïve CD4+ T cells led to development of cells with a Treg phenotype; it also induced proliferation of a CD25+ CD127 FoxP3+ T cells, which expressed CTLA-4, interleukin-10, and transforming growth factor–β and had suppressive activities. In contrast to dendritic cells, normal CMFs required exogenous interleukin-2 to induce proliferation of naturally occurring Treg cells. Induction of Treg cells by normal CMFs required major histocompatibility complex class II and prostaglandin E2. CMFs from patients with inflammatory bowel diseases had reduced capacity to induce active Treg 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 Treg cells might promote pathogenesis of inflammatory bowel diseases.

Section snippets

Antibodies and Reagents

Please see Supplementary Materials and Methods.

Human Colonic Tissue and Primary CMF Culture

For CMF isolation, fresh human colonic mucosal sections were obtained from discarded surgical tissue in compliance with protocols approved by the University of Texas Medical Branch Institutional Review Board. Areas of uninvolved colonic tissue from patients undergoing colectomy for colon cancer were used as the source for normal CMFs (N-CMFs). CMFs were also isolated from inflamed colonic tissues from patients with ulcerative colitis (UC) or

CMFs Stabilize FoxP3 Expression in nTreg and Induce Their Proliferation in Presence of IL-2

We showed previously that CMFs induce proliferation of resting CD4+ T cells isolated from peripheral blood,12 which is also known to contain CD4+ CD25high FoxP3+nTreg cells. Thus, we investigated the interaction of the Treg and CMFs isolated from normal colonic mucosa.

Previously, we reported that, in culture, MHC class II expression by CMF drastically decreases when compared to that on acutely isolated cells and the higher levels demonstrated in situ.12 Thus, in all experiments, primary CMFs

Discussion

Antigen presenting cells play a critical role in maintaining the balance between tolerance and inflammation in the gut.1, 10, 11, 12 The role of professional antigen presenting cells, such as DCs and macrophages, in the differentiation of T cells and regulation of their activity has been well-investigated.1, 10, 11, 12, 25 Little is known about the role of intestinal stromal cells in these processes. It has been established that stromal cells are important contributors to immune homeostasis and

Acknowledgments

Drs Reyes and Powell shared senior authorship in this work.

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    Conflicts of interest The authors disclose no conflicts.

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