Selective Accumulation of Pro-Inflammatory T Cells in the Intestine Contributes to the Resistance to Autoimmune Demyelinating Disease

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.

Fecal Microbiota Transplantation in Neurological Disorders

“…It is hypothesized that subsequently elevated Th1 and 17 cause inflammation in the CNS and increased blood-brain barrier permeability, leading in turn to exacerbation of the inflammation of the CNS (Dendrou et al, 2015). Modulation of the gut microbiota to induce more Treg cells could lead to less activation of pathogenic T-cells (Berer et al, 2014). Interestingly, gavage with a human gut-derived commensal strain Prevotella histicola resulted in a decreased incidence of disease in a mouse model of MS (Mangalam et al, 2017).…”

Autoimmune host–microbiota interactions at barrier sites and beyond

“…Additional work demonstrated that B10.S mice, which are genetically resistant to EAE induction, harbor significantly higher populations of T H 17 cells in the intestine compared to SJL/J EAE-susceptible mice. Blockade of the gut-homing integrin α 4 β 7 abrogated resistance in B10.S mice [65]. The link between intestinal immune cells and autoimmunity outside the gut remains to be fully elucidated.…”

Environmental enrichment alleviates the deleterious effects of stress in experimental autoimmune encephalomyelitis

“…Animal studies give a possible link between gut inflammation and MS: intestinal barrier dysfunction occurs at the onset of monophasic EAE 14 and a pro-inflammatory response in the gut has been shown to trigger EAE 15,16 . Conversely, the sequestration of Th17 cells in the gut confers resistance to EAE 17 . Together, these studies suggest a sequence of events involving the gut in the pathogenesis of EAE: (i) initial expansion and activation of T-cell in gut-associated lymphoid tissues, leading to (ii) recruitment of auto-antibody-producing B cells and (iii) migration to brain draining cervical nodes to finally trigger autoimmune encephalomyelitis.…”