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.

Leukocyte adhesion deficiency type 1 (LAD-1) is a rare disease resulting from mutations in the gene encoding for the common β-chain of the β2-integrin family (CD18). The most prominent clinical symptoms are profound leukocytosis and high susceptibility to infections. Patients with LAD-1 are prone to develop autoimmune diseases, but the molecular and cellular mechanisms that result in coexisting immunodeficiency and autoimmunity are still unresolved. CD4+FOXP3+ Treg are known for their essential role in preventing autoimmunity. To understand the role of Treg in LAD-1 development and manifestation of autoimmunity, we generated mice specifically lacking CD18 on Treg (CD18Foxp3), resulting in defective LFA-1 expression. Here, we demonstrate a crucial role of LFA-1 on Treg to maintain immune homeostasis by modifying T cell-DC interactions and CD4+ T cell activation. Treg-specific CD18 deletion did not impair Treg migration into extralymphatic organs, but it resulted in shorter interactions of Treg with DC. In vivo, CD18Foxp3 mice developed spontaneous hyperplasia in lymphatic organs and diffuse inflammation of the skin and in multiple internal organs. Thus, LFA-1 on Treg is required for the maintenance of immune homeostasis.

SH2B3 (SH2B adaptor protein 3) is an adaptor protein that negatively regulates cytokine signaling and cell proliferation. A common missense single nucleotide polymorphism in SH2B3 (rs3184504) results in substitution of tryptophan (Trp) for arginine (Arg) at amino acid 262 and is a top association signal for hypertension in human genome-wide association studies. Whether this variant is causal for hypertension, and if so, the mechanism by which it impacts pathogenesis is unknown.
We used CRISPR-Cas9 technology to create mice homozygous for the major (Arg/Arg) and minor (Trp/Trp) alleles of this SH2B3 polymorphism. Mice underwent angiotensin II (Ang II) infusion to evaluate differences in blood pressure (BP) elevation and end-organ damage including albuminuria and renal fibrosis. Cytokine production and Stat4 phosphorylation was also assessed in Arg/Arg and Trp/Trp T cells.
Trp/Trp mice exhibit 10 mmHg higher systolic BP during chronic Ang II infusion compared to Arg/Arg controls. Renal injury and perivascular fibrosis are exacerbated in Trp/Trp mice compared to Arg/Arg controls following Ang II infusion. Renal and ex vivo stimulated splenic CD8+ T cells from Ang II-infused Trp/Trp mice produce significantly more interferon gamma (IFNg) compared to Arg/Arg controls. Interleukin-12 (IL-12)-induced IFNg production is greater in Trp/Trp compared to Arg/Arg CD8+ T cells. In addition, IL-12 enhances Stat4 phosphorylation to a greater degree in Trp/Trp compared to Arg/Arg CD8+ T cells, suggesting that Trp-encoding SH2B3 exhibits less negative regulation of IL-12 signaling to promote IFNg production. Finally, we demonstrated that a multi-SNP model genetically predicting increased SH2B3 expression in lymphocytes is inversely associated with hypertension and hypertensive chronic kidney disease in humans..
Taken together, these results suggest that the Trp encoding allele of rs3184504 is causal for BP elevation and renal dysfunction, in part through loss of SH2B3-mediated repression of T cell IL-12 signaling leading to enhanced IFNg production.

An immunological hallmark of visceral leishmaniasis (VL), caused by Leishmania donovani, is profound immunosuppression. However, the molecular basis for this immune dysfunction has remained ill defined. Since dendritic cells (DCs) normally initiate antileishmanial immune responses, we investigated whether DCs are dysregulated during L. donovani infection and assessed its role in immunosuppression. Accordingly, we determined the regulatory effect of L. donovani on DCs. Notably, it is still unclear whether L. donovani activates or suppresses DCs. In addition, the molecular mechanism and the relevant receptor (or receptors) mediating the immunoregulatory effect of L. donovani on DCs are largely undefined. Here, we report that L. donovani inhibited DC activation/maturation by transmitting inhibitory signals through the T cell immunoglobulin and mucin protein-3 (TIM-3) receptor and thereby suppressed antileishmanial immune responses. L. donovani in fact triggered TIM-3 phosphorylation in DCs, which in turn recruited and activated a nonreceptor tyrosine kinase, Btk. Btk then inhibited DC activation/maturation by suppressing the NF-κB pathway in an interleukin-10 (IL-10)-dependent manner. Treatment with TIM-3-specific blocking antibody or suppressed expression of TIM-3 or downstream effector Btk made DCs resistant to the inhibitory effects of L. donovani. Adoptive transfer experiments further demonstrated that TIM-3-mediated L. donovani-induced inhibition of DCs plays a crucial role in the suppression of the antileishmanial immune response in vivo. These findings identify TIM-3 as a new regulator of the antileishmanial immune response and demonstrate a unique mechanism for host immunosuppression associated with L. donovani infection. IMPORTANCE Visceral leishmaniasis (VL), a poverty-related disease caused by Leishmania donovani, is ranked by the World Health Organization as the second largest killer parasitic disease in the world. The protective immune response against VL is primarily regulated by dendritic cells (DCs), which upon activation/maturation initiate an antileishmanial immune response. However, it remains obscure whether L. donovani promotes or inhibits DC activation. In addition, the receptor through which L. donovani exerts immunoregulatory effect on DCs is ill defined. Here, we for the first time report that L. donovani inhibits DC activation and maturation via the T cell immunoglobulin and mucin protein-3 (TIM-3) receptor and thereby attenuates the capacity of DCs to trigger antileishmanial immune responses in vivo. In fact, we demonstrate here that suppression of TIM-3 expression in DCs augments antileishmanial immunity. Our study uncovers a unique mechanism by which L. donovani subverts host immune responses and suggests TIM-3 as a potential new target for immunotherapy against VL.

Life stress may influence symptom onset and severity in certain gastrointestinal disorders in association with a dysregulated intestinal barrier. It has been widely accepted that stress triggers the hypothalamus‑pituitary‑adrenal (HPA) axis, releasing corticosterone, which promotes intestinal permeability. In response, colonic inflammation alters mucosal immune homeostasis and destroys the colonic architecture, leading to severe intestinal diseases. Endogenous substance P (SP) does not inhibit the initial extent of the HPA axis response to restraint stress, but it reduces the duration of the stress, suggesting that SP plays an important role in the transition between acute and chronic stress. The present study aimed to investigate the effect of two groups of mice exposed to stress, including acute and chronic stress. The corticosterone was evaluated by ELISA, colon samples were obtained to detected polymorphonuclear cells by hematoxylin and eosin staining, goblet and mast cells were identified by immunocytochemistry and cytokine‑producing CD4+ T cells were analyzed by flow cytometry assays, adhesion proteins in the colon epithelium by western blotting and serum SP levels by ELISA. The results demonstrated an increase in the number of polymorphonuclear, goblet and mast cells, a decrease in claudin‑1 expression and an elevation in E‑cadherin expression during acute stress. Increased E‑cadherin expression was also detected during chronic stress. Moreover, it was found that acute stress caused a shift towards a predominantly anti‑inflammatory immune response (T helper 2 cells), as shown by the increase in the percentage of CD4+/IL‑6+ and CD4+/IL4+ lymphocytes in the lamina propria and the increase in serum SP. In conclusion, this response promoted colonic protection during acute stress.