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Abstract
Myelin-specific, pro-inflammatory TH17 cells are widely regarded as the drivers of experimental autoimmune encephalomyelitis (EAE), an animal model for Multiple sclerosis (MS). The factors, responsible for the generation and maintenance of TH17 cells as well as their participation in the pathogenic cascade leading to the demyelinating disease, have been studied extensively. However, how these harmful autoreactive cells are controlled in vivo remains unclear. By comparing TCR transgenic mice on a disease susceptible and a disease resistant genetic background, we show here that pathogenic TH17 cells are sequestered within the intestine of spontaneous EAE resistant B10.S mice. Disease resistant B10.S mice harbored higher frequencies of TH17 cells in the intestine compared to EAE susceptible SJL/J mice. Moreover, transferred TH17 cells selectively migrated to intestinal lymphoid organs of B10.S mice. The sequestration of TH17 cells in the gut was partially dependent on the gut homing receptor α4β7-mediated adhesion to the intestine. Administration of α4β7 blocking-antibodies increased the peripheral availability of TH17 cells, resulting in increased EAE severity after immunization in B10.S mice. Together, these results support the concept that the intestine is a check-point for controlling pathogenic, organ-specific T cells.
Highlights
Evidence suggests that autoreactive T cells are commonly present in the healthy immune repertoire, but are kept in check by numerous tolerance mechanisms
We recently described a transgenic mouse strain that expresses a myelin oligodendrocyte glycoprotein (MOG)-specific T cell receptor (TCR) on the SJL/J genetic background (RR mice)
We describe a mechanism of tolerance to the development of spontaneous EAE
Summary
Evidence suggests that autoreactive T cells are commonly present in the healthy immune repertoire, but are kept in check by numerous tolerance mechanisms. Understanding the mechanisms of self-tolerance, which limits the aberrant activation of self-reactive T cells, is crucial for the development of strategies to treat autoimmune diseases, like Multiple sclerosis (MS). From the animal models of MS, it became evident that distinct T helper cell subsets, such as IFN-c-producing TH1 and IL-17-producing TH17 cells, either alone or in combination are capable of mediating a neurological disease in animals, resembling the human disease [3,4,5,6]. Transfer of polarized TH17 cells induced neurological disease, supporting the idea that this T helper cell subset plays an important role in EAE pathogenesis [3,6]. Despite the extensive knowledge about the generation and maintenance of TH17 cells, how these cells are regulated in vivo during autoimmune disease settings needs further investigation
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