PD-1 Ligand Expression by Human Colonic Myofibroblasts/Fibroblasts Regulates CD4+ T-Cell Activity

Iryna Pinchuk, Jamal I. Saada, Ellen J. Beswick, Gushyalatha Boya, Suimin Qiu, Randy C. Mifflin, Gottumukkala S. Raju, Victor Reyes, Don W. Powell

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
JournalGastroenterology
Volume135
Issue number4
DOIs
StatePublished - Oct 2008

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Myofibroblasts
Fibroblasts
Ligands
T-Lymphocytes
Interleukin-2
Helper-Inducer T-Lymphocytes
Cell Proliferation
Peripheral Tolerance
Adaptive Immunity
Coculture Techniques
Major Histocompatibility Complex
Confocal Microscopy
Colon
Fluorescence
Western Blotting
Enzyme-Linked Immunosorbent Assay
Cytokines
Inflammation
Phenotype

ASJC Scopus subject areas

  • Gastroenterology

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PD-1 Ligand Expression by Human Colonic Myofibroblasts/Fibroblasts Regulates CD4+ T-Cell Activity. / Pinchuk, Iryna; Saada, Jamal I.; Beswick, Ellen J.; Boya, Gushyalatha; Qiu, Suimin; Mifflin, Randy C.; Raju, Gottumukkala S.; Reyes, Victor; Powell, Don W.

In: Gastroenterology, Vol. 135, No. 4, 10.2008.

Research output: Contribution to journalArticle

Pinchuk, Iryna ; Saada, Jamal I. ; Beswick, Ellen J. ; Boya, Gushyalatha ; Qiu, Suimin ; Mifflin, Randy C. ; Raju, Gottumukkala S. ; Reyes, Victor ; Powell, Don W. / PD-1 Ligand Expression by Human Colonic Myofibroblasts/Fibroblasts Regulates CD4+ T-Cell Activity. In: Gastroenterology. 2008 ; Vol. 135, No. 4.
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T1 - PD-1 Ligand Expression by Human Colonic Myofibroblasts/Fibroblasts Regulates CD4+ T-Cell Activity

AU - Pinchuk, Iryna

AU - Saada, Jamal I.

AU - Beswick, Ellen J.

AU - Boya, Gushyalatha

AU - Qiu, Suimin

AU - Mifflin, Randy C.

AU - Raju, Gottumukkala S.

AU - Reyes, Victor

AU - Powell, Don W.

PY - 2008/10

Y1 - 2008/10

N2 - 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.

AB - 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.

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