The expression and function of costimulatory molecules B7H and B7-H1 on colonic epithelial cells

doi:10.1053/j.gastro.2004.02.004

Gastroenterology

Volume 126, Issue 5, May 2004, Pages 1347-1357

https://doi.org/10.1053/j.gastro.2004.02.004 Get rights and content

Abstract

$Background & Aims:$ Previous studies have suggested that intestinal epithelial cells (IECs) may function as antigen-presenting cells for CD4⁺ and CD8⁺ T cells. However, these cells fail to express conventional costimulatory molecules (CD80, CD86), leading to the possibility that antigen presented by normal IECs could result in anergy. Other members of the B7 family have recently been identified. B7h interacts with inducible costimulator (ICOS) on T cells and provides a positive signal, whereas B7-H1 and B7-DC interact with PD-1 and transmit an inhibitory signal. Our aim was to determine whether IECs express novel B7 family members and whether these molecules play a role in IEC:T-cell interactions. $Methods:$ B7h and B7-H1 expression was assessed in isolated IECs and IEC lines. The functional role of B7h and B7-H1 in the interaction between IECs and T cells was assessed in coculture experiments using purified anti-B7h or B7-H1 monoclonal antibodies (mAbs), B7h immunoglobulin (Ig), or B7-H1 fusion proteins. $Results:$ B7h and B7-H1 messenger RNA was detected in IEC lines and IECs from healthy controls and patients with inflammatory bowel disease (IBD). IECs from patients with IBD but not healthy controls expressed B7h and B7-H1 protein on their surface. Proliferation of IEC-stimulated T cells was inhibited only by B7h immunoglobulin treatment, whereas interferon gamma secretion in these cocultures was inhibited by both anti-B7h mAb and B7h Ig. No difference was seen between IBD or normal IEC populations. $Conclusions:$ These data suggest that the B7h-ICOS costimulatory pathway may be important in IEC:T-cell interactions.

Section snippets

Cell lines

HT-29, an intestinal epithelial cell line of human colonic adenocarcinoma origin, and the T84 human carcinoma cell line derived from a lung metastasis of a colon carcinoma were obtained from the American Type Culture Collection (Rockville, MD). HT-29 cells, in a subconfluent state, were stimulated with 100 U/mL of recombinant human IFN-γ (InterMune Pharmaceuticals, Inc., Palo Alto, CA) or 10 ng/mL TNF-α (Biosource, Camarillo, CA) for 48 hours. Single cell suspensions of HT-29 cells were then

Expression of B7H and b7-h1 molecules in human colonic epithelial cell lines

We first assessed B7h and B7-H1 expression at the mRNA level in the colonic epithelial cell line HT-29. In HT-29, the expression of B7h mRNA was detected constitutively. It increased after TNF-α (10 ng/mL) stimulation and decreased after IFN-γ (100 U/mL) stimulation, consistent with previous data in the murine fibroblast cell line 3T3.15 B7-H1 mRNA expression was induced after both IFN-γ and TNF-α stimulation (Figure 1). We also investigated the PD-1 ligand, B7-DC, mRNA expression. In HT-29,

Discussion

In previous studies, we have shown that IECs have the capacity to present antigens to T cells.1, 2, 3 In general, antigen-specific activation of CD4⁺ T cells requires presentation by antigen-presenting cells and a second signal via the B7-CD28 costimulatory pathway.7, 8, 9, 10 Epithelial cells in the normal mucosa lack conventional costimulatory molecules (CD80 and CD86)11, 12; therefore, the interaction of naive CD4⁺ mucosal T cells with these epithelial cells would result in anergy or

References (36)

X.Y. Yio et al.
Characterization of a 180-kDa intestinal epithelial cell membrane glycoprotein, gp180. A candidate molecule mediating T cell-epithelial cell interactions
J Biol Chem
(1997)
M. Allez et al.
Expansion of CD8+ T cells with regulatory function after interaction with intestinal epithelial cells
Gastroenterology
(2002)
A. Nakazawa et al.
Functional expression of costimulatory molecule CD86 on epithelial cells in the inflamed colonic mucosa
Gastroenterology
(1999)
M.M. Swallow et al.
B7h, a novel costimulatory homolog of B7.1 and B7.2, is induced by TNFalpha
Immunity
(1999)
H. Tamura et al.
B7-H1 costimulation preferentially enhances CD28-independent T-helper cell function
Blood
(2001)
H. Nishimura et al.
Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor
Immunity
(1999)
P. Youngnak et al.
Differential binding properties of B7-H1 and B7-DC to programmed death-1
Biochem Biophys Res Commun
(2003)
L. Mayer et al.
Evidence for function of Ia molecules on gut epithelial cells in man
J Exp Med
(1987)
Y. Li et al.
Human intestinal epithelial cell-induced CD8+ T cell activation is mediated through CD8 and the activation of CD8-associated p56lck
J Exp Med
(1995)
L. Mayer et al.
Lack of induction of suppressor T cells by intestinal epithelial cells from patients with inflammatory bowel disease
J Clin Invest
(1990)

L.S. Toy et al.

Defective Expression of gp180, a novel CD8 ligand on intestinal epithelial cells, in inflammatory bowel disease

J Clin Invest

(1997)

A. Aruffo et al.

Molecular cloning of a CD28 cDNA by a high-efficiency COS cell expression system

Proc Natl Acad Sci U S A

(1987)

R.H. Schwartz

A cell culture model for T lymphocyte clonal anergy

Science

(1990)

M. Azuma et al.

B70 antigen is a second ligand for CTLA4 and CD28

Nature

(1993)

K.S. Hathcock et al.

Identification of an alternative CTLA-4 ligand costimulatory for T cell activation

Science

(1993)

S. Bloom et al.

Adhesion molecules intercellular adhesion molecule-1 (ICAM-1), ICAM-3 and B7 are not expressed by epithelium in normal or inflamed colon

Clin Exp Immunol

(1995)

I.R. Sanderson et al.

Differential regulation of B7 mRNA in enterocytes and lymphoid cells

Immunology

(1993)

H.W. Mages et al.

Molecular cloning and characterization of murine ICOS and identification of B7h as ICOS ligand

Eur J Immunol

(2000)

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^☆: Supported by National Institutes of Health grants AI 23504, AI 24671, and AI 44236 (to L.M.), Crohn’s and Colitis Foundation fellowship awards (to I.D. and M.A.), and the Danish Medical Research Agency (to J.B.).

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Basic-alimentary tractThe expression and function of costimulatory molecules B7H and B7-H1 on colonic epithelial cells☆

Abstract

Section snippets

Cell lines

Expression of B7H and b7-h1 molecules in human colonic epithelial cell lines

Discussion

J Biol Chem

Gastroenterology

Gastroenterology

Immunity

Blood

Immunity

Biochem Biophys Res Commun

Evidence for function of Ia molecules on gut epithelial cells in man

J Exp Med

Human intestinal epithelial cell-induced CD8+ T cell activation is mediated through CD8 and the activation of CD8-associated p56lck

J Exp Med

Lack of induction of suppressor T cells by intestinal epithelial cells from patients with inflammatory bowel disease

J Clin Invest

Defective Expression of gp180, a novel CD8 ligand on intestinal epithelial cells, in inflammatory bowel disease

J Clin Invest

Molecular cloning of a CD28 cDNA by a high-efficiency COS cell expression system

Proc Natl Acad Sci U S A

A cell culture model for T lymphocyte clonal anergy

Science

B70 antigen is a second ligand for CTLA4 and CD28

Nature

Identification of an alternative CTLA-4 ligand costimulatory for T cell activation

Science

Adhesion molecules intercellular adhesion molecule-1 (ICAM-1), ICAM-3 and B7 are not expressed by epithelium in normal or inflamed colon

Clin Exp Immunol

Differential regulation of B7 mRNA in enterocytes and lymphoid cells

Immunology

Molecular cloning and characterization of murine ICOS and identification of B7h as ICOS ligand

Eur J Immunol

Basic-alimentary tract
The expression and function of costimulatory molecules B7H and B7-H1 on colonic epithelial cells☆