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?v Integrin expression by DCs is required for Th17 cell differentiation and development of experimental autoimmune encephalomyelitis in mice.

ABSTRACT: Th17 cells are a distinct lineage of T helper cells that protect the body from bacterial and fungal infection. However, Th17 cells also contribute to inflammatory and autoimmune disorders such as multiple sclerosis. Th17 cell generation requires exposure of naive T cells to the cytokine TGF-? in combination with proinflammatory cytokines. Here we show that differentiation of Th17 cells is also critically dependent on ?v integrins. In mice, lack of integrin ?v in the immune system resulted in loss of Th17 cells in the intestine and lymphoid tissues. It also led to protection from experimental autoimmune encephalomyelitis (EAE). Further analysis indicated that ?v integrins on DCs activated latent TGF-? during T cell stimulation and thereby promoted differentiation of Th17 cells. Furthermore, pharmacologic inhibition of ?v integrins using cyclic RGD peptides blocked TGF-? activation and Th17 cell generation in vitro and protected mice from EAE. These data demonstrate that activation of TGF-? by ?v-expressing myeloid cells may be a critical step in the generation of Th17 cells and suggest that ?v integrins could be therapeutic targets in autoimmune disease.

SUBMITTER: Acharya M

PROVIDER: S-EPMC2993596 | biostudies-literature | 2010 Dec

REPOSITORIES: biostudies-literature

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αv Integrin expression by DCs is required for Th17 cell differentiation and development of experimental autoimmune encephalomyelitis in mice.

Acharya Mridu M Mukhopadhyay Subhankar S Païdassi Helena H Jamil Tahseen T Chow Camille C Kissler Stephan S Stuart Lynda M LM Hynes Richard O RO Lacy-Hulbert Adam A

The Journal of clinical investigation 20101122 12

Th17 cells are a distinct lineage of T helper cells that protect the body from bacterial and fungal infection. However, Th17 cells also contribute to inflammatory and autoimmune disorders such as multiple sclerosis. Th17 cell generation requires exposure of naive T cells to the cytokine TGF-β in combination with proinflammatory cytokines. Here we show that differentiation of Th17 cells is also critically dependent on αv integrins. In mice, lack of integrin αv in the immune system resulted in los ...[more]

PMID: 21099114

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Project description:BACKGROUND:Toll-like receptor 4 (TLR4) is well known for activating the innate immune system; however, it is also highly expressed in adaptive immune cells, such as CD4+ T-helper 17 (Th17) cells, which play a key role in multiple sclerosis (MS) pathology. However, the function and governing mechanism of TLR4 in Th17 remain unclear. METHODS:The changes of TLR4 in CD4+ T cells from MS patients and experimental autoimmune encephalomyelitis (EAE) mice were tested. TLR4-deficient (TLR4-/-) naïve T cells were induced in vitro and transferred into Rag1-/- mice to measure Th17 differentiation and EAE pathology. DNA sequence analyses combining with deletion fragments and mutation analyses, chromatin immunoprecipitation (ChIP), and electrophoretic mobility shift assay (EMSA) were used to explore the mechanism of TLR4 signaling pathway in regulating Th17 differentiation. RESULTS:The levels of TLR4 were increased in CD4+ Th17 cells both from MS patients and EAE mice, as well as during Th17 differentiation in vitro. TLR4-/- CD4+ naïve T cells inhibited their differentiation into Th17, and transfer of TLR4-/- CD4+ naïve T cells into Rag1-/- mice was defective in promoting EAE, characterized by less demyelination and Th17 infiltration in the spinal cord. TLR4 signal enhanced Th17 differentiation by activating RelA, downregulating the expression of miR-30a, a negative regulator of Th17 differentiation. Inhibition of RelA activity increased miR-30a level, but decreased Th17 differentiation rate. Furthermore, RelA directly regulated the expression of miR-30a via specific binding to a conserved element of miR-30a gene. CONCLUSIONS:TLR4-/- CD4+ naïve T cells are inadequate in differentiating to Th17 cells both in vitro and in vivo. TLR4-RelA-miR-30a signal pathway regulates Th17 differentiation via direct binding of RelA to the regulatory element of miR-30a gene. Our results indicate modulating TLR4-RelA-miR-30a signal in Th17 may be a therapeutic target for Th17-mediated neurodegeneration in neuroinflammatory diseases.

Dataset Information

?v Integrin expression by DCs is required for Th17 cell differentiation and development of experimental autoimmune encephalomyelitis in mice.

Publications

αv Integrin expression by DCs is required for Th17 cell differentiation and development of experimental autoimmune encephalomyelitis in mice.

Similar Datasets

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