Mucosal surfaces are in continuous contact with microbes. Toll-like receptors (TLRs) mediate recognition of microbial molecules to eliminate pathogens. In contrast, we demonstrate here that the prominent gut commensal, Bacteroides fragilis, activates the TLR pathway on T lymphocytes to establish host-microbial symbiosis. TLR2 deletion on CD4+ T cells results in anti-microbial immune responses that reduce B. fragilis colonization of a unique mucosal niche during homeostasis. A symbiosis factor (PSA) of B. fragilis activates TLR2 directly on Foxp3+ regulatory T cells through a novel process to engender mucosal tolerance. Remarkably, B. fragilis lacking PSA is unable to restrain host immune responses and is defective in niche-specific mucosal colonization. Therefore, unlike pathogens whose TLR ligands trigger inflammation, some commensal bacteria exploit the TLR pathway to actively suppress immune reactions. We propose that the immunologic distinction between pathogens and the microbiota is mediated not solely by host mechanisms, but also through specialized molecules evolved by symbiotic bacteria that enable commensal colonization.

Beginning in 1970, a committee was constituted under the auspices of the World Health Organization (WHO) to catalog primary immunodeficiencies. Twenty years later, the International Union of Immunological Societies (IUIS) took the remit of this committee. The current report details the categorization and listing of 354 (as of February 2017) inborn errors of immunity. The growth and increasing complexity of the field have been impressive, encompassing an increasing variety of conditions, and the classification described here will serve as a critical reference for immunologists and researchers worldwide.

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Background The genetic etiologies of the hyper-IgE syndromes are diverse. Approximately 60-70% of patients with hyper-IgE syndrome have dominant mutations in STAT3, and a single patient was reported to have a homozygous TYK2 mutation. In the remaining hyper-IgE syndrome patients, the genetic etiology has not yet been identified. Methods We performed genome-wide single nucleotide polymorphism analysis for nine subjects with autosomal recessive hyper-IgE syndrome to locate copy number variations and homozygous haplotypes. Homozygosity mapping was performed with twelve subjects from seven additional families. The candidate gene was analyzed by genomic and cDNA sequencing to identify causative alleles in a total of 27 patients with autosomal recessive hyper-IgE syndrome. Findings Subtelomeric microdeletions were identified in six subjects at the terminus of chromosome 9p. In all patients the deleted interval involved DOCK8, encoding a protein implicated in the regulation of the actin cytoskeleton. Sequencing of subjects without large deletions revealed 16 patients from nine unrelated families with distinct homozygous mutations in DOCK8 causing premature termination, frameshift, splice site disruption, single exon- and micro-deletions. DOCK8 deficiency was associated with impaired activation of CD4+ and CD8+ T cells. Interpretation Autosomal recessive mutations in DOCK8 are responsible for many, though not all, cases of autosomal recessive hyper-IgE syndrome. DOCK8 disruption is associated with a phenotype of severe cellular immunodeficiency characterized by susceptibility to viral infections, atopic eczema, defective T cell activation and TH17 cell differentiation; and impaired eosinophil homeostasis and dysregulation of IgE.