Regulatory T Cell-Derived TGF-ß1 Controls Multiple Checkpoints Governing Allergy and Autoimmunity.

The mechanisms by which regulatory T (Treg) cells differentially control allergic and autoimmune responses remain unclear. We show that Treg cells in food allergy (FA) had decreased expression of transforming growth factor beta 1 (TGF-ß1) because of interleukin-4 (IL-4)- and signal transducer and activator of transciription-6 (STAT6)-dependent inhibition of Tgfb1 transcription. These changes were modeled by Treg cell-specific Tgfb1 monoallelic inactivation, which induced allergic dysregulation by impairing microbiota-dependent retinoic acid receptor-related orphan receptor gamma t (ROR-γt)+ Treg cell differentiation. This dysregulation was rescued by treatment with Clostridiales species, which upregulated Tgfb1 expression in Treg cells. Biallelic deficiency precipitated fatal autoimmunity with intense autoantibody production and dysregulated T follicular helper and B cell responses. These results identify a privileged role of Treg cell-derived TGF-ß1 in regulating allergy and autoimmunity at distinct checkpoints in a Tgfb1 gene dose- and microbiota-dependent manner.

Lipid-antigen presentation by CD1d(+) B cells is essential for the maintenance of invariant natural killer T cells.

B cells perform many immunological functions, including presenting lipid antigen to CD1d-restricted invariant natural killer T (iNKT) cells, known to contribute to maintaining tolerance in autoimmunity. Patients with systemic lupus erythematous (SLE) display dysregulated B cell responses and reduced peripheral iNKT cell frequencies. The significance of these defects and how they relate to SLE pathogenesis remain elusive. We report that B cells are essential for iNKT cell expansion and activation in healthy donors but fail to exert a similar effect in SLE patients. Defective B cell-mediated stimulation of iNKT cells in SLE patients was associated with altered CD1d recycling, a defect recapitulated in B cells from healthy donors after stimulation with interferon-α (IFN-α) and anti-immunoglobulin (Ig). iNKT cell number and function were restored in SLE patients responding to anti-CD20 treatment upon normalization of CD1d expression exclusively in repopulated immature B cells. We propose that healthy B cells are pivotal for iNKT cell homeostasis.

Oral immunotherapy induces IgG antibodies that act through FcγRIIb to suppress IgE-mediated hypersensitivity.

BACKGROUND: Food-induced anaphylaxis is triggered by specific IgE antibodies. Paradoxically, some subjects with significant IgE levels can ingest allergenic foods without incident. Similarly, subjects completing oral immunotherapy (OIT) tolerate food challenges despite persistent high-titer food-specific IgE. OBJECTIVE: We sought to test whether IgG antibodies induced by food immunotherapy prevent food-induced anaphylaxis and whether this occurs through the inhibitory receptor FcγRIIb. METHODS: Food allergy-susceptible Il4raF709 mice were enterally sensitized to ovalbumin (OVA). Similarly sensitized IgE-deficient (IgE(-/-)) Il4raF709 mice, which can ingest OVA without anaphylaxis, were subjected to a high-dose enteral OVA desensitization protocol (OIT). Sera from both groups were tested for the ability to activate or inhibit bone marrow mast cells (BMMCs) exposed to allergen or to passively transfer allergy to naive hosts. In parallel experiments sera obtained from patients with peanut allergy before and after undergoing OIT were interrogated for their ability to enhance or suppress peanut-induced activation in an indirect assay by using basophils from nonallergic donors. RESULTS: Il4raF709 mice exhibited strong OVA-specific IgE responses. Their sera efficiently sensitized BMMCs for activation by antigen challenge. Sera from Il4raF709/IgE(-/-) mice subjected to OVA OIT suppressed BMMC responses. This inhibition was IgG mediated and FcγRIIb dependent. Similarly, pre-OIT but not post-OIT sera from patients efficiently sensitized basophils for peanut-induced activation. IgG antibodies in post-OIT sera suppressed basophil activation by pre-OIT sera. This inhibition was blocked by antibodies against FcγRII. CONCLUSION: Food-specific IgG antibodies, such as those induced during OIT, inhibit IgE-mediated reactions. Strategies that favor IgG responses might prove useful in the management of food allergy.

Long-Term Outcome of Peanut Oral Immunotherapy Facilitated Initially by Omalizumab.

BACKGROUND: We successfully used omalizumab to facilitate peanut oral immunotherapy (OIT) in children with reactivity to ≤50mg peanut protein and with high peanut IgE (median, 229 kU/L). OBJECTIVE: We report on long-term OIT outcomes in these patients, including dosing changes, adverse events, peanut immunoglobulin changes, and quality of life (QoL). METHODS: Patients were followed for up to 72 months (67 months of maintenance). Outcomes were collected on peanut dose amount, form, and frequency, as well as adverse events, (QoL), and laboratory studies. RESULTS: Of 13 patients initially enrolled, 7 patients (54%) continued on peanut OIT through month 72; 6 (46%) discontinued therapy because of adverse reactions. Maintenance peanut protein dose varied between 500 and 3500mg. Most patients consumed different peanut-containing products. All patients experienced at least 1 adverse event, and 1 patient developed eosinophilic esophagitis. Peanut-IgE, Arah1-IgE and Arah2-IgE, peanut-SPT, peanut-IgE:IgE ratio, and Arah2-IgE:Arah2-IgG4 ratio decreased on OIT. Peanut-IgG4, Arah1-IgG4, and Arah2-IgG4 initially increased on OIT and then decreased, though not falling to baseline levels. In patients who stopped OIT, there was a trend for reversal of these biomarker changes. Higher peanut-IgE and Arah2-IgE at study month 12 were associated with discontinuation. Patient and parent QoL improved from baseline, even in patients who discontinued OIT. CONCLUSIONS: Although adjunctive omalizumab allowed for faster and successful desensitization in patients with high peanut-IgE, almost half of patients discontinued OIT within 72 months because of reactions. Patients who stopped therapy had higher month 12 peanut-IgE and Arah2-IgE. It is possible that these patients might benefit from longer omalizumab administration.

Author Correction: Microbiota therapy acts via a regulatory T cell MyD88/RORγt pathway to suppress food allergy.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Microbiota therapy acts via a regulatory T cell MyD88/RORγt pathway to suppress food allergy.

The role of dysbiosis in food allergy (FA) remains unclear. We found that dysbiotic fecal microbiota in FA infants evolved compositionally over time and failed to protect against FA in mice. Infants and mice with FA had decreased IgA and increased IgE binding to fecal bacteria, indicative of a broader breakdown of oral tolerance than hitherto appreciated. Therapy with Clostridiales species impacted by dysbiosis, either as a consortium or as monotherapy with Subdoligranulum variabile, suppressed FA in mice as did a separate immunomodulatory Bacteroidales consortium. Bacteriotherapy induced expression by regulatory T (Treg) cells of the transcription factor ROR-γt in a MyD88-dependent manner, which was deficient in FA infants and mice and ineffectively induced by their microbiota. Deletion of Myd88 or Rorc in Treg cells abrogated protection by bacteriotherapy. Thus, commensals activate a MyD88/ROR-γt pathway in nascent Treg cells to protect against FA, while dysbiosis impairs this regulatory response to promote disease.

Antigen-specific Treg cells in immunological tolerance: implications for allergic diseases.

Allergic diseases are chronic inflammatory disorders in which there is failure to mount effective tolerogenic immune responses to inciting allergens. The alarming rise in the prevalence of allergic diseases in recent decades has spurred investigations to elucidate the mechanisms of breakdown in tolerance in these disorders and means of restoring it. Tolerance to allergens is critically dependent on the generation of allergen-specific regulatory T (Treg) cells, which mediate a state of sustained non-responsiveness to the offending allergen. In this review, we summarize recent advances in our understanding of mechanisms governing the generation and function of allergen-specific Treg cells and their subversion in allergic diseases. We will also outline approaches to harness allergen-specific Treg cell responses to restore tolerance in these disorders.