Dataset Information

Extracellular matrix-associated cytokines regulate CD4+ effector T-cell responses in the human intestinal mucosa.

ABSTRACT: Extracellular matrix (stroma) regulation of mucosal T-cell function is incompletely understood. In this study, we uncovered a role for intestinal stromal products in the innate regulation of effector T cells. Stroma-conditioned media (S-CM) derived from the normal human intestinal stroma (transforming growth factor-? (TGF-?)(hi)/interleukin (IL)-6(lo)/IL-1?(lo)) significantly downregulated T-cell proliferation and interferon-? (IFN-?) production compared with S-CM derived from the inflamed Crohn's mucosa (TGF-?(hi)/IL-6(hi)/IL-1?(hi)). Antibody neutralization studies showed that TGF-? in normal S-CM inhibited T-cell proliferation and IFN-? production, whereas IL-6 plus IL-1? in Crohn's S-CM promoted T-cell proliferation, and IL-1? alone promoted IFN-? and IL-17 release. Importantly, normal S-CM inhibited T-bet expression, whereas Crohn's S-CM activated signal transducer and activator of transcription 3, suggesting that discordant T-cell responses are regulated at the transcription factor and signaling levels. These findings implicate stromal TGF-? in the downregulation of T-cell 2 responses in the normal intestinal mucosa, and stromal IL-6 and IL-1? in the promotion of Th1 and Th17 responses in the inflamed Crohn's mucosa, suggesting an innate regulatory function for the intestinal extracellular matrix.

SUBMITTER: Huff KR

PROVIDER: S-EPMC3118864 | biostudies-literature | 2011 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Extracellular matrix-associated cytokines regulate CD4+ effector T-cell responses in the human intestinal mucosa.

Huff K R KR Akhtar L N LN Fox A L AL Cannon J A JA Smith P D PD Smythies L E LE

Mucosal immunology 20110112 4

Extracellular matrix (stroma) regulation of mucosal T-cell function is incompletely understood. In this study, we uncovered a role for intestinal stromal products in the innate regulation of effector T cells. Stroma-conditioned media (S-CM) derived from the normal human intestinal stroma (transforming growth factor-β (TGF-β)(hi)/interleukin (IL)-6(lo)/IL-1β(lo)) significantly downregulated T-cell proliferation and interferon-γ (IFN-γ) production compared with S-CM derived from the inflamed Crohn ...[more]

PMID: 21228771

Similar Datasets

Project description:Innate lymphoid cells (ILCs) are a recently characterized family of immune cells that have critical roles in cytokine-mediated regulation of intestinal epithelial cell barrier integrity. Alterations in ILC responses are associated with multiple chronic human diseases, including inflammatory bowel disease, implicating a role for ILCs in disease pathogenesis. Owing to an inability to target ILCs selectively, experimental studies assessing ILC function have predominantly used mice lacking adaptive immune cells. However, in lymphocyte-sufficient hosts ILCs are vastly outnumbered by CD4(+) T cells, which express similar profiles of effector cytokines. Therefore, the function of ILCs in the presence of adaptive immunity and their potential to influence adaptive immune cell responses remain unknown. To test this, we used genetic or antibody-mediated depletion strategies to target murine ILCs in the presence of an adaptive immune system. We show that loss of retinoic-acid-receptor-related orphan receptor-?t-positive (ROR?t(+)) ILCs was associated with dysregulated adaptive immune cell responses against commensal bacteria and low-grade systemic inflammation. Remarkably, ILC-mediated regulation of adaptive immune cells occurred independently of interleukin (IL)-17A, IL-22 or IL-23. Genome-wide transcriptional profiling and functional analyses revealed that ROR?t(+) ILCs express major histocompatibility complex class II (MHCII) and can process and present antigen. However, rather than inducing T-cell proliferation, ILCs acted to limit commensal bacteria-specific CD4(+) T-cell responses. Consistent with this, selective deletion of MHCII in murine ROR?t(+) ILCs resulted in dysregulated commensal bacteria-dependent CD4(+) T-cell responses that promoted spontaneous intestinal inflammation. These data identify that ILCs maintain intestinal homeostasis through MHCII-dependent interactions with CD4(+) T cells that limit pathological adaptive immune cell responses to commensal bacteria.

Dataset Information

Extracellular matrix-associated cytokines regulate CD4+ effector T-cell responses in the human intestinal mucosa.

Publications

Extracellular matrix-associated cytokines regulate CD4+ effector T-cell responses in the human intestinal mucosa.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets