A commensal bacterial product elicits and modulates migratory capacity of CD39⁺CD4 T regulatory subsets in the suppression of neuroinflammation

Abstract

Tolerance established by host-commensal interactions regulates host immunity at both local mucosal and systemic levels. The intestinal commensal strain Bacteroides fragilis elicits immune tolerance, at least in part, via the expression capsular polysaccharide A (PSA). How such niche-specific commensal microbial elements regulate extra-intestinal immune responses, as in the brain, remains largely unknown. We have recently shown that oral treatment with PSA suppresses neuro-inflammation elicited during experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis. This protection is dependent upon the expansion of immune-regulatory CD4 T cells (Treg) expressing CD39, an ectonucleotidase. Here, we further show that CD39 modulation of purinergic signals enhances migratory phenotypes of both total CD4 T cells and Foxp3(+) CD4 Tregs at central nervous system (CNS) lymphoid-draining sites in EAE in vivo and promotes their migration in vitro. These changes are noted during PSA treatment, which leads to heightened accumulation of CD39(+) CD4 Tregs in the CNS. Deficiency of CD39 abrogates accumulation of Treg during EAE, and is accompanied by elevated Th1/Th17 signals in the CNS and in gut-associated lymphoid tissues. Our results demonstrate that immune-modulatory commensal bacterial products impact the migratory patterns of CD4 Treg during CNS autoimmunity via the regulation of CD39. These observations provide clues as to how intestinal commensal microbiome is able to modulate Treg functions and impact host immunity in the distal site.

Tumor-infiltrating CD39+γδTregs are novel immunosuppressive T cells in human colorectal cancer

“…3D). Interestingly, tumor-infiltrating CD39 C gdT cells rendered much greater immunosuppressive property than other immunosuppressive T cells, including CD39 C CD4 C20, 21 and CD39 C CD8 C T cells 18,22,23 (Fig. 3C and D).…”

The Microbiome and Neurologic Disease: Past and Future of a 2-Way Interaction

“…Although genetic susceptibility is a factor that may determine disease, other risk factors are also necessary, in particular, environmental triggers such as those associated with known risk factors. We, among other investigators, explored the effects of the gut microbiota in experimental autoimmune encephalomyelitis (EAE) models of MS and proposed the idea that the composition of the gut microbiota is relevant for the balance of the proinflammatory and anti-inflammatory cell subpopulations that result in disease induction or protection [9][10][11][12][13][14][15][16][17]. This special issue covers the most recent literature on the experimental models and the clinical evidence for changes in the gut microbiota observed in patients with MS. Tremlett and Waubant [18] explore the microbiota of pediatric MS cases.…”

The chicken or the egg dilemma: intestinal dysbiosis in multiple sclerosis

“…Our laboratory has previously shown that oral treatment with PSA protects mice against EAE through the induction of regulatory CD39 + T cells and Foxp3 + T regulatory cells (Tregs) (24,26,27). B. fragilis colonization also improves the integrity of the barrier (9).…”

“…Furthermore, treatment with oral antibiotics also reduce significantly the severity of EAE (30,31). The experimental evidence gathered using animal model studies indicate the effects of the microbiota in the regulation of EAE in animals (24,(26)(27)(28)(32)(33)(34)(35)(36). Furthermore, gut microbes, such as B. fragilis and Lactobacillus rhamnosus have been shown to interact with neurons in the enteric nervous system (ENS) directly and affect their function (37).…”