Breast milk is a complex mixture of nutrients and bioactives that promote infant development and decrease the incidence of chronic inflammatory disease. We investigated the role of one milk-derived bioactive, Immunoglobulin A (IgA) on the developing small intestinal microbiota and immune system. We demonstrate that early in life, milk-derived IgA suppressed colonization of the small intestine by Enterobacteriaceae and regulated the maturation of the small intestinal epithelium and the development of intestinal IL-17-producing CD4 + T cells. Enterobacteriaceae - specific CD4 + T cells, induced in the first weeks of life in the absence of milk-derived IgA, persisted in the intestine as memory T cells that can contribute to inflammatory disease later in life. Our study suggests that milk-derived IgA shapes mucosal immunity by regulating the neonatal microbiota thus preventing the development of long-lived intestinal microbiota-specific T cells.

Background IL4, IL5, IL13, and IL17-producing CD4 T helper 2 (Th2)-cells and IL17-producing CD4 T helper 17 (Th17)-cells contribute to chronic eosinophilic and neutrophilic airway inflammation in asthma and allergic airway inflammation. Chemokines and their receptors are upregulated in Th2/Th17-mediated inflammation. However, the ability of CXCR1 and CXCR2 modulate Th2 and Th17-cell-mediated allergic lung inflammation has not been reported. Methods Mice sensitized and challenged with cat dander extract (CDE) mount a vigorous Th2-Th17-mediated allergic lung inflammation. Allosteric inhibitor of CXCR1 and CXCR2, ladarixin was orally administered in this model. The ability of ladarixin to modulate allergen-challenge induced recruitment of CXCR1 and CXCR2-expressing Th2 and Th17-cells and allergic lung inflammation were examined. Results Allergen challenge in sensitized mice increased mRNA expression levels of Il4, Il5, Il13, Il6, Il1β, Tgfβ1, Il17, Il23, Gata3, and Rorc , and induced allergic lung inflammation characterized by recruitment of CXCR1- and CXCR2-expressing Th2-cells, Th17-cells, neutrophils, and eosinophils. Allosteric inhibition of CXCR1 and CXCR2 vigorously blocked each of these pro-inflammatory effects of allergen challenge. CXCL chemokines induced a CXCR1 and CXCR2-dependent proliferation of IL4, IL5, IL13, and IL17 expressing T-cells. Conclusion Allosteric inhibition of CXCR1 and CXCR2 abrogates blocks recruitment of CXCR1- and CXCR2-expressing Th2-cells, Th17-cells, neutrophils, and eosinophils in this mouse model of allergic lung inflammation. We suggest that the ability of allosteric inhibition of CXCR1 and CXCR2 to abrogate Th2 and Th17-mediated allergic inflammation should be investigated in humans.

Loss of antimicrobial proteins such as REG3 family members compromises the integrity of the intestinal barrier. Here, we demonstrate that overproduction of REG3 proteins can also be detrimental by reducing a protective species in the microbiota. Patients with inflammatory bowel disease (IBD) experiencing flares displayed heightened levels of secreted REG3 proteins that mediated depletion of Enterococcus faecium (Efm) from the gut microbiota. Efm inoculation of mice ameliorated intestinal inflammation through activation of the innate immune receptor NOD2, which was associated with the bacterial DL-endopeptidase SagA that generates NOD2-stimulating muropeptides. NOD2 activation in myeloid cells induced interleukin-1β (IL-1β) secretion to increase the proportion of IL-22-producing CD4+ T helper cells and innate lymphoid cells that promote tissue repair. Finally, Efm was unable to protect mice carrying a NOD2 gene variant commonly found in IBD patients. Our findings demonstrate that inflammation self-perpetuates by causing aberrant antimicrobial activity that disrupts symbiotic relationships with gut microbes.
Copyright © 2023 Elsevier Inc. All rights reserved.

Atherosclerosis is a chronic inflammatory disease caused by deposition of oxidative low-density lipoprotein (LDL) in the arterial intima which triggers the innate immune response through myeloid cells such as macrophages. Regulatory T cells (Tregs) play an important role in controlling the progression or regression of atherosclerosis by resolving macrophage-mediated inflammatory functions. Interleukin-2 (IL-2) signaling is essential for homeostasis of Tregs. Since recombinant IL-2 has an unfavorable pharmacokinetic profile limiting its therapeutic use, we constructed a fusion protein, designated HCW9302, containing two IL-2 domains linked by an extracellular tissue factor domain. We found that HCW9302 exhibited a longer serum half-life with an approximately 1000-fold higher affinity for the IL-2Rα than IL-2. HCW9302 could be administered to mice at a dosing range that expanded and activated Tregs but not CD4+ effector T cells. In an ApoE-/- mouse model, HCW9302 treatment curtailed the progression of atherosclerosis through Treg activation and expansion, M2 macrophage polarization and myeloid-derived suppressor cell induction. HCW9302 treatment also lessened inflammatory responses in the aorta. Thus, HCW9302 is a potential therapeutic agent to expand and activate Tregs for treatment of inflammatory and autoimmune diseases.
Copyright © 2023 Zhu, Li, George, Spanoudis, Gilkes, Shrestha, Liu, Kong, You, Echeverri, Li, Wang, Chaturvedi, Muniz, Egan, Rhode and Wong.

Functionally distinct CD4+ helper T (Th) cell subsets, including Th1, Th2, Th17, and regulatory T cells (Treg), play a pivotal role in the regulation of acquired immunity. Although the key proteins involved in the regulation of Th cell differentiation have already been identified how the proteogenomic landscape changes during the Th cell activation remains unclear. To address this issue, we characterized proteogenomic signatures of differentiation to each Th cell subsets by RNA sequencing and liquid chromatography-assisted mass spectrometry, which enabled us to simultaneously quantify more than 10,000 protein-coding transcripts and 8,000 proteins in a single-shot. The results indicated that T cell receptor activation affected almost half of the transcript and protein levels in a low correlative and gene-specific manner, and specific cytokine treatments modified the transcript and protein profiles in a manner specific to each Th cell subsets: Th17 and Tregs particularly exhibited unique proteogenomic signatures compared to other Th cell subsets. Interestingly, the in-depth proteome data revealed that mRNA profiles alone were not enough to delineate functional changes during Th cell activation, suggesting that the proteogenomic dataset obtained in this study serves as a unique and indispensable data resource for understanding the comprehensive molecular mechanisms underlying effector Th cell differentiation.
© The Author(s) 2022. Published by Oxford University Press on behalf of Kazusa DNA Research Institute.