PD-1 ligand expression by human colonic myofibroblasts/fibroblasts regulates CD4+ T-cell activity

Gastroenterology. 2008 Oct;135(4):1228-1237, 1237.e1-2. doi: 10.1053/j.gastro.2008.07.016. Epub 2008 Jul 17.

Abstract

Background & aims: A prominent role for inhibitory molecules PD-L1 and PD-L2 in peripheral tolerance has been proposed. However, the phenotype and function of PD-L-expressing cells in human gut remains unclear. Recent studies suggest that colonic myofibroblasts (CMFs) and fibroblasts are important in the switch from acute inflammation to adaptive immunity. In the normal human colon, CMFs represent a distinct population of major histocompatibility complex class II(+) cells involved in the regulation of mucosal CD4(+) T-cell responses.

Methods: PD-L1 and PD-L2 expression on human CMFs was determined using Western blot, fluorescence-activated cell sorter analysis and confocal microscopy. Lymphoproliferation assays and cytokine enzyme-linked immunosorbent assays were used to evaluate the role of B7 costimulators expressed by CMFs with regard to the regulation of preactivated T-helper cell responses.

Results: We demonstrate here the expression of PD-L1/2 molecules by normal human CMF and fibroblasts in situ and in culture. Both molecules support suppressive functions of CMFs in the regulation of activated CD4(+) T-helper cell proliferative responses; blocking this interaction reverses the suppressive effect of CMFs on T-cell proliferation and leads to increased production of the major T-cell growth factor, interleukin (IL)-2. PD-L1/2-mediated CMF suppressive functions are mainly due to the inhibition of IL-2 production, because supplementation of the coculture media with exogenous IL-2 led to partial recovery of activated T-cell proliferation.

Conclusions: Our data suggest that stromal myofibroblasts and fibroblasts may limit T-helper cell proliferative activity in the gut and, thus, might play a prominent role in mucosal intestinal tolerance.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, CD / genetics
  • Antigens, CD / immunology*
  • Antigens, CD / metabolism
  • B7-H1 Antigen
  • CD4-Positive T-Lymphocytes / cytology
  • CD4-Positive T-Lymphocytes / immunology*
  • Cell Communication / immunology
  • Cell Division / drug effects
  • Cell Division / immunology
  • Cells, Cultured
  • Colon / cytology
  • Colon / immunology*
  • Fibroblasts / cytology
  • Fibroblasts / physiology*
  • Humans
  • Immune Tolerance / physiology*
  • Intercellular Signaling Peptides and Proteins / genetics
  • Intercellular Signaling Peptides and Proteins / immunology
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Interleukin-2 / pharmacology
  • Phenotype
  • Programmed Cell Death 1 Ligand 2 Protein
  • RNA, Small Interfering
  • Stromal Cells / cytology
  • Stromal Cells / physiology
  • Thy-1 Antigens / metabolism

Substances

  • Antigens, CD
  • B7-H1 Antigen
  • CD274 protein, human
  • Intercellular Signaling Peptides and Proteins
  • Interleukin-2
  • PDCD1LG2 protein, human
  • Programmed Cell Death 1 Ligand 2 Protein
  • RNA, Small Interfering
  • Thy-1 Antigens