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.

Keywords: :

• regulatory T cells
• commensal bacteria
• neuro-inflammation
• immuno-regulation
• EAE/MS
• cell migration
• ectonucleotidase
• Th1/Th17
• gut-brain axis

This article refers to:

10.4161/gmic.29797

Disclosure of Potential Conflicts of Interest

No potential conflict of interest was disclosed.

Acknowledgments

We thank Dr Randolph J Noelle (Dartmouth College; King’s College London, UK) for research guidance. We thank DartLab (Dartmouth College) members Dr Jacqueline Y Smith, Dr. Daniel W Mielcarz, John DeLong, Gary A Ward, Alan J Bergeron, and Nathan Martin for technical support of flow cytometry and critical guidance of research. We thank Kathryn A Bennett (Dartmouth College) for animal care. We thank Dr Azizul Haque (Dartmouth College) for critical review. This work was supported by National Multiple Sclerosis Society grant RG 4662A2/1 and National Institute of Allergy and Infectious Diseases grants (1R41 AI110170-01 and 1R56 AI098282-01A1). S.C.R. was supported by National Institute of Health grants (P01 HL087203 and U19 AI090959) and Helmsley Charitable Trust.

Author Contributions

Y.W. and S.B-H. performed experiments and did the research. Y.W. designed research, prepared the figures and wrote the manuscript. K.M.T. and J.O-R. contributed research design and data. M.C. and E.J.K. contributed experiments. D.L.K. graciously provided PSA and critical comments on the research. S.C.R. contributed key mouse strain and critical comments on the manuscript. L.H.K. supervised the research and reviewed the manuscript.