Modulation of host responses by oral commensal bacteria.

Immunomodulatory commensal bacteria are proposed to be essential for maintaining healthy tissues, having multiple roles including priming immune responses to ensure rapid and efficient defences against pathogens. The default state of oral tissues, like the gut, is one of inflammation which may be balanced by regulatory mechanisms and the activities of anti-inflammatory resident bacteria that modulate Toll-like receptor (TLR) signalling or NF-κB activation, or influence the development and activities of immune cells. However, the widespread ability of normal resident organisms to suppress inflammation could impose an unsustainable burden on the immune system and compromise responses to pathogens. Immunosuppressive resident bacteria have been isolated from the mouth and, for example, may constitute 30% of the resident streptococci in plaque or on the tongue. Their roles in oral health and dysbiosis remain to be determined. A wide range of bacterial components and/or products can mediate immunomodulatory activity, raising the possibility of development of alternative strategies for therapy and health promotion using probiotics, prebiotics, or commensal-derived immunomodulatory molecules

MAIT cells are imprinted by the microbiota in early life and promote tissue repair

How early-life colonization and subsequent exposure to the microbiota affect long-term tissue immunity remains poorly understood. Here, we show that the development of mucosal-associated invariant T (MAIT) cells relies on a specific temporal window, after which MAIT cell development is permanently impaired. This imprinting depends on early-life exposure to defined microbes that synthesize riboflavin-derived antigens. In adults, cutaneous MAIT cells are a dominant population of interleukin-17A (IL-17A)-producing lymphocytes, which display a distinct transcriptional signature and can subsequently respond to skin commensals in an IL-1-, IL-18-, and antigen-dependent manner. Consequently, local activation of cutaneous MAIT cells promotes wound healing. Together, our work uncovers a privileged interaction between defined members of the microbiota and MAIT cells, which sequentially controls both tissue-imprinting and subsequent responses to injury

Regulatory role of suppressive motifs from commensal DNA

The microbiota contributes to the induction of both effector and regulatory responses in the gastrointestinal tract. However, the mechanisms controlling these distinct properties remain poorly understood. We previously showed that commensal DNA promotes intestinal immunity. Here, we find that the capacity of bacterial DNA to stimulate immune responses is species specific and correlated with the frequency of motifs known to exert immunosuppressive function. In particular, we show that the DNA of Lactobacillus species, including various probiotics, are enriched in suppressive motifs able to inhibit lamina propria DC activation. In addition, immunosuppressive oligonucleotides sustain T(reg) cell conversion during inflammation and limit pathogen-induced immunopathology and colitis. Altogether, our findings identify DNA suppressive motifs as a molecular ligand expressed by commensals and support the idea that a balance between stimulatory and regulatory DNA motifs contributes to the induction of controlled immune responses in the GI tract and gut immune homeostasis. Further, our findings suggest that the endogenous regulatory capacity of DNA motifs enriched in some commensal bacteria could be exploited for therapeutic purposes

Transcription factor EGR2 controls homing and pathogenicity of T H 17 cells in the central nervous system

CD4 T helper 17 (T 17) cells protect barrier tissues but also trigger autoimmunity. The mechanisms behind these opposing processes remain unclear. Here, we found that the transcription factor EGR2 controlled the transcriptional program of pathogenic T 17 cells in the central nervous system (CNS) but not that of protective T 17 cells at barrier sites. EGR2 was significantly elevated in myelin-reactive CD4 T cells from patients with multiple sclerosis and mice with autoimmune neuroinflammation. The EGR2 transcriptional program was intricately woven within the T 17 cell transcriptional regulatory network and showed high interconnectivity with core T 17 cell-specific transcription factors. Mechanistically, EGR2 enhanced T 17 cell differentiation and myeloid cell recruitment to the CNS by upregulating pathogenesis-associated genes and myelomonocytic chemokines. T cell-specific deletion of Egr2 attenuated neuroinflammation without compromising the host's ability to control infections. Our study shows that EGR2 regulates tissue-specific and disease-specific functions in pathogenic T 17 cells in the CNS