Activin A-Expressing Polymorphonuclear Myeloid-Derived Suppressor Cells Infiltrate Skeletal and Cardiac Muscle and Promote Cancer Cachexia.

Cachexia is a major cause of death in cancer and leads to wasting of cardiac and skeletal muscle, as well as adipose tissue. Various cellular and soluble mediators have been postulated in driving cachexia; however, the specific mechanisms behind this muscle wasting remain poorly understood. In this study, we found polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) to be critical for the development of cancer-associated cachexia. Significant expansion of PMN-MDSCs was observed in the cardiac and skeletal muscles of cachectic murine models. Importantly, the depletion of this cell subset, using depleting anti-Ly6G Abs, attenuated this cachectic phenotype. To elucidate the mechanistic involvement of PMN-MDSCs in cachexia, we examined major mediators, that is, IL-6, TNF-α, and arginase 1. By employing a PMN-MDSC-specific Cre-recombinase mouse model, we showed that PMN-MDSCs were not maintained by IL-6 signaling. In addition, PMN-MDSC-mediated cardiac and skeletal muscle loss was not abrogated by deficiency in TNF-α or arginase 1. Alternatively, we found PMN-MDSCs to be critical producers of activin A in cachexia, which was noticeably elevated in cachectic murine serum. Moreover, inhibition of the activin A signaling pathway completely protected against cardiac and skeletal muscle loss. Collectively, we demonstrate that PMN-MDSCs are active producers of activin A, which in turn induces cachectic muscle loss. Targeting this immune/hormonal axis will allow the development of novel therapeutic interventions for patients afflicted with this debilitating syndrome.

Oxidized Low-Density Lipoprotein Accumulation Suppresses Glycolysis and Attenuates the Macrophage Inflammatory Response by Diverting Transcription from the HIF-1α to the Nrf2 Pathway.

Lipid accumulation in macrophages (Mφs) is a hallmark of atherosclerosis, yet how lipid accumulation affects inflammatory responses through rewiring of Mφ metabolism is poorly understood. We modeled lipid accumulation in cultured wild-type mouse thioglycolate-elicited peritoneal Mφs and bone marrow-derived Mφs with conditional (Lyz2-Cre) or complete genetic deficiency of Vhl, Hif1a, Nos2, and Nfe2l2. Transfection studies employed RAW264.7 cells. Mφs were cultured for 24 h with oxidized low-density lipoprotein (oxLDL) or cholesterol and then were stimulated with LPS. Transcriptomics revealed that oxLDL accumulation in Mφs downregulated inflammatory, hypoxia, and cholesterol metabolism pathways, whereas the antioxidant pathway, fatty acid oxidation, and ABC family proteins were upregulated. Metabolomics and extracellular metabolic flux assays showed that oxLDL accumulation suppressed LPS-induced glycolysis. Intracellular lipid accumulation in Mφs impaired LPS-induced inflammation by reducing both hypoxia-inducible factor 1-α (HIF-1α) stability and transactivation capacity; thus, the phenotype was not rescued in Vhl-/- Mφs. Intracellular lipid accumulation in Mφs also enhanced LPS-induced NF erythroid 2-related factor 2 (Nrf2)-mediated antioxidative defense that destabilizes HIF-1α, and Nrf2-deficient Mφs resisted the inhibitory effects of lipid accumulation on glycolysis and inflammatory gene expression. Furthermore, oxLDL shifted NADPH consumption from HIF-1α- to Nrf2-regulated apoenzymes. Thus, we postulate that repurposing NADPH consumption from HIF-1α to Nrf2 transcriptional pathways is critical in modulating inflammatory responses in Mφs with accumulated intracellular lipid. The relevance of our in vitro models was established by comparative transcriptomic analyses, which revealed that Mφs cultured with oxLDL and stimulated with LPS shared similar inflammatory and metabolic profiles with foamy Mφs derived from the atherosclerotic mouse and human aorta.

Maternal diet supplementation with high-docosahexaenoic-acid canola oil, along with arachidonic acid, promotes immune system development in allergy-prone BALB/c mouse offspring at 3 weeks of age.

PURPOSE: To study the effects of feeding docosahexaenoic acid (DHA, derived from novel canola oil), with same amount of arachidonic acid (ARA), supplemented diet to lactating dams on the immune system development of suckled offspring using a T helper type-2 (Th2)-dominant BALB/c mouse. METHODS: Dams received nutritionally complete control (no ARA or DHA) or DHA + ARA diet (1% DHA and 1% ARA of total fatty acids) from 5 days pre-parturition to the end of 3-week suckling period. After euthanization, relevant tissues were collected to study fatty acids, splenocyte phenotype and function (ex vivo cytokines with/without lipopolysaccharide (LPS, bacterial challenge) or phorbol myristate acetate + ionomycin (PMAi) stimulation). RESULTS: Feeding dams a DHA diet significantly increased the mammary gland milk phospholipid concentration of DHA and ARA. This resulted in 60% higher DHA levels in splenocyte phospholipids of the pups although ARA levels showed no difference. In dams fed DHA diet, significantly higher proportion of CD27+ cytotoxic T cell (CTL) and CXCR3+ CCR6- Th (enriched in Th1) were observed than control, but there were no differences in the splenocyte function upon PMAi (non-specific lymphocyte stimulant) stimulation. Pups from DHA-fed dams showed significantly higher IL-1ß, IFN-γ and TNF-α (inflammatory cytokines) by LPS-stimulated splenocytes. This may be due to higher proportion of CD86+ macrophages and B cells (all p's < 0.05) in these pups, which may influence T cell polarization. CONCLUSION: Plant-based source of DHA in maternal diet resulted in higher ex vivo production of inflammatory cytokines by splenocytes due to change in their phenotype, and this can skew T cell towards Th1 response in a Th2-dominant BALB/c mouse.

Low-fat dairy consumption improves intestinal immune function more than high-fat dairy in a diet-induced swine model of insulin resistance.

PURPOSE: To understand the effects of consuming high-fat and low-fat dairy products on postprandial cardiometabolic risk factors and intestinal immune function, we used an established low birthweight (LBW) swine model of diet-induced insulin resistance. METHODS: LBW piglets were randomized to consume one of the 3 experimental high fat diets and were fed for a total of 7 weeks: (1) Control high fat (LBW-CHF), (2) CHF diet supplemented with 3 servings of high-fat dairy (LBW-HFDairy) and (3) CHF diet supplemented with 3 servings of low-fat dairy (LBW-LFDairy). As comparison groups, normal birthweight (NBW) piglets were fed a CHF (NBW-CHF) or standard pig grower diet (NBW-Chow). At 11 weeks of age, all piglets underwent an established modified oral glucose and fat tolerance test. At 12 weeks of age, piglets were euthanized and ex vivo cytokine production by cells isolated from mesenteric lymph node (MLN) stimulated with mitogens was assessed. RESULTS: Dairy consumption did not modulate postprandial plasma lipid, inflammatory markers and glucose concentrations. A lower production of IL-2 and TNF-α after pokeweed mitogen (PWM) stimulation was observed in LBW-CHF vs NBW-Chow (P < 0.05), suggesting impaired MLN T cell function. While feeding high-fat dairy had minimal effects, feeding low-fat dairy significantly improved the production of IL-2 and TNF-α after PWM stimulation (P < 0.05). CONCLUSIONS: Irrespective of fat content, dairy had a neutral effect on postprandial cardiometabolic risk factors. Low-fat dairy products improved intestinal T cell function to a greater extent than high-fat dairy in this swine model of obesity and insulin resistance.

Sex Differences Distinctly Impact High-Fat Diet-Induced Immune Dysfunction in Wistar Rats.

BACKGROUND: Immune function is altered during obesity. Moreover, males and females across different species demonstrate distinct susceptibility to several diseases. However, less is known regarding the interplay between high-fat diet (HFD) and sex in the context of immune function. OBJECTIVES: The objective was to determine sex differences on immune function in response to an HFD compared with a control low-fat diet (LFD) in Wistar rats. METHODS: At 5 wk of age, male and female Wistar rats were randomly assigned to 1 of 2 diets for 9 wk: ad libitum control LFD (20 kcal% fat, 53 kcal% carbohydrate, and 27 kcal% protein) or HFD (50 kcal% fat, 23 kcal% carbohydrate, and 27 kcal% protein). At 13 wk of age, rats were killed and splenocytes were isolated. Immune cell subsets were determined by flow cytometry. Immune cell function was determined by measuring the ex vivo cytokine production following stimulation with mitogens. Two-factor ANOVA was used to assess the main effect of sex, diet, and their interaction. RESULTS: Males gained more weight than females (410 ± 46 vs. 219 ± 45 g), independently of diet (P-sex < 0.01). The HFD led to a lower production of IL-2 while increasing the production of IL-10 (both P-diet ≤ 0.05), independently of sex. HFD-fed females had increased production of cytokines (IL-2 and IL-6) after stimulation with phorbol 12-myristate 13-acetate plus ionomycin (PMA+I), as well as a higher T-helper (Th) 1:Th2 balance compared with HFD-fed males (all P < 0.05). Males fed the HFD had significantly lower production of IL-2 upon stimulation compared with all other groups. CONCLUSIONS: Female Wistar rats developed a milder obesity phenotype and maintained enhanced cytokine production compared with males fed the HFD. Sex differences modulate immune function in the context of high-fat feeding and it should be considered in research design to establish personalized health-related recommendations.

Expanding antigen-specific regulatory networks to treat autoimmunity.

Regulatory T cells hold promise as targets for therapeutic intervention in autoimmunity, but approaches capable of expanding antigen-specific regulatory T cells in vivo are currently not available. Here we show that systemic delivery of nanoparticles coated with autoimmune-disease-relevant peptides bound to major histocompatibility complex class II (pMHCII) molecules triggers the generation and expansion of antigen-specific regulatory CD4(+) T cell type 1 (TR1)-like cells in different mouse models, including mice humanized with lymphocytes from patients, leading to resolution of established autoimmune phenomena. Ten pMHCII-based nanomedicines show similar biological effects, regardless of genetic background, prevalence of the cognate T-cell population or MHC restriction. These nanomedicines promote the differentiation of disease-primed autoreactive T cells into TR1-like cells, which in turn suppress autoantigen-loaded antigen-presenting cells and drive the differentiation of cognate B cells into disease-suppressing regulatory B cells, without compromising systemic immunity. pMHCII-based nanomedicines thus represent a new class of drugs, potentially useful for treating a broad spectrum of autoimmune conditions in a disease-specific manner.

Aryl hydrocarbon receptor agonist indigo protects against obesity-related insulin resistance through modulation of intestinal and metabolic tissue immunity.

BACKGROUND/OBJECTIVES: Low-grade chronic inflammation in visceral adipose tissue and the intestines are important drivers of obesity associated insulin resistance. Bioactive compounds derived from plants are an important source of potential novel therapies for the treatment of chronic diseases. In search for new immune based treatments of obesity associated insulin resistance, we screened for tissue relevant anti-inflammatory properties in 20 plant-based extracts. METHODS: We screened 20 plant-based extracts to assess for preferential production of IL-10 compared to TNFα, specifically targetting metabolic tissues, including the visceral adipose tissue. We assessed the therapeutic potential of the strongest anti-inflammatory compound, indigo, in the C57BL/6J diet-induced obesity mouse model with supplementation for up to 16 weeks by measuring changes in body weight, glucose and insulin tolerance, and gut barrier function. We also utilized flow cytometry, quantitative PCR, enzyme-linked immunosorbent assay (ELISA), and histology to measure changes to immune cells populations and cytokine profiles in the intestine, visceral adipose tissue (VAT), and liver. 16SrRNA sequencing was performed to examine gut microbial differences induced by indigo supplementation. RESULTS: We identifed indigo, an aryl hydrocarbon receptor (AhR) ligand agonist, as a potent inducer of IL-10 and IL-22, which protects against high-fat diet (HFD)-induced insulin resistance and fatty liver disease in the diet-induced obesity model. Therapeutic actions were mechanistically linked to decreased inflammatory immune cell tone in the intestine, VAT and liver. Specifically, indigo increased Lactobacillus bacteria and elicited IL-22 production in the gut, which improved intestinal barrier permeability and reduced endotoxemia. These changes were associated with increased IL-10 production by immune cells residing in liver and VAT. CONCLUSIONS: Indigo is a naturally occurring AhR ligand with anti-inflammatory properties that effectively protects against HFD-induced glucose dysregulation. Compounds derived from indigo or those with similar properties could represent novel therapies for diseases associated with obesity-related metabolic tissue inflammation.

Reversal of autoimmunity by boosting memory-like autoregulatory T cells.

Blunting autoreactivity without compromising immunity remains an elusive goal in the treatment of autoimmunity. We show that progression to autoimmune diabetes results in the conversion of naive low-avidity autoreactive CD8(+) T cells into memory-like autoregulatory cells that can be expanded in vivo with nanoparticles coated with disease-relevant peptide-major histocompatibility complexes (pMHC-NP). Treatment of NOD mice with monospecific pMHC-NPs expanded cognate autoregulatory T cells, suppressed the recruitment of noncognate specificities, prevented disease in prediabetic mice, and restored normoglycemia in diabetic animals. pMHC-NP therapy was inconsequential in mice engineered to bear an immune system unresponsive to the corresponding epitope, owing to absence of epitope-experienced autoregulatory T cells. pMHC-NP-expanded autoregulatory T cells suppressed local presentation of autoantigens in an interferon-gamma-, indoleamine 2,3-dioxygenase-, and perforin-dependent manner. Nanoparticles coated with human diabetes-relevant pHLA complexes restored normoglycemia in a humanized model of diabetes. These observations expose a paradigm in the pathogenesis of autoimmunity amenable for therapeutic intervention.

Antidiabetogenic MHC class II promotes the differentiation of MHC-promiscuous autoreactive T cells into FOXP3+ regulatory T cells.

Polymorphisms in MHC class II molecules, in particular around ß-chain position-57 (ß57), afford susceptibility/resistance to multiple autoimmune diseases, including type 1 diabetes, through obscure mechanisms. Here, we show that the antidiabetogenic MHC class II molecule I-A(b) affords diabetes resistance by promoting the differentiation of MHC-promiscuous autoreactive CD4(+) T cells into disease-suppressing natural regulatory T cells, in a ß56-67-regulated manner. We compared the tolerogenic and antidiabetogenic properties of CD11c promoter-driven transgenes encoding I-A(b) or a form of I-A(b) carrying residues 56-67 of I-Aß(g7) (I-A(b-g7)) in wild-type nonobese diabetic (NOD) mice, as well as NOD mice coexpressing a diabetogenic and I-A(g7)-restricted, but MHC-promiscuous T-cell receptor (4.1). Both I-A transgenes protected NOD and 4.1-NOD mice from diabetes. However, whereas I-A(b) induced 4.1-CD4(+) thymocyte deletion and 4.1-CD4(+)Foxp3(+) regulatory T-cell development, I-A(b-g7) promoted 4.1-CD4(+)Foxp3(+) Treg development without inducing clonal deletion. Furthermore, non-T-cell receptor transgenic NOD.CD11cP-I-A(b) and NOD.CD11cP-IA(b-g7) mice both exported regulatory T cells with superior antidiabetogenic properties than wild-type NOD mice. We propose that I-A(b), and possibly other protective MHC class II molecules, afford disease resistance by engaging a naturally occurring constellation of MHC-promiscuous autoreactive T-cell clonotypes, promoting their deviation into autoregulatory T cells.

Dendritic cell-dependent in vivo generation of autoregulatory T cells by antidiabetogenic MHC class II.

Several mechanisms have been proposed to explain how certain MHC class II molecules afford dominant resistance to autoimmune diseases like type 1 diabetes (T1D). However, it remains unclear how protective MHC types can blunt autoreactive T cell responses directed against a diverse repertoire of autoantigenic epitopes presented by disease-promoting MHCs. In this study, we show that expression of I-E on dendritic cells (DCs) of NOD mice promotes the differentiation of MHC promiscuous autoreactive CD4(+) clonotypes into antidiabetogenic autoregulatory T cells. We expressed an I-Eα(kloxP) transgene in NOD mice and used cell type-specific I-E ablation to show that I-E-expressing DCs, but not B cells, promote the generation of autoreactive CD4(+)Foxp3(+) regulatory T cells (Tregs) and their accumulation in the pancreas-draining lymph nodes. There, these Tregs suppress the presentation of ß cell Ags to naive autoreactive CD4(+) and CD8(+) T cells restricted by diabetogenic MHC molecules in an I-E-independent manner. Whereas selective removal of I-E on DCs abrogated autoregulatory Treg formation and T1D protection, selective removal of I-E on B cells was inconsequential. These results explain how certain MHC class II molecules can completely suppress antigenically complex autoimmune responses in an Ag-nonspecific manner.

IL-2 promotes the function of memory-like autoregulatory CD8+ T cells but suppresses their development via FoxP3+ Treg cells.

IL-2 plays a critical role in both effector T-cell development and FoxP3(+) CD4(+) Treg-cell homeostasis. A reduction in Il2 transcription results in impaired FoxP3(+) CD4(+) Treg-cell recruitment and function, and accounts for the association between murine Il2 and type 1 diabetes (T1D). The progression of T1D elicits a disease-countering negative feedback regulatory loop that involves the differentiation of low-avidity autoreactive CD8(+) T cells into memory-like autoregulatory T cells in a CD4(+) Th-dependent manner. Since these auto-regulatory T cells express IL-2Rß (CD122), we hypothesized that their development might also be regulated by IL-2. Here, we investigate the effects of differences in IL-2 expression on this autoregulatory subset. We show that decreased IL-2 production impairs the regulatory capacity of memory-like autoregulatory CD8(+) CD122(+) T cells. Surprisingly, we also find that a reduction in IL-2 production capacity increases memory autoregulatory CD8(+) T-cell formation indirectly, by decreasing the development and function of FoxP3(+) Treg cells in nonobese diabetic mice. These results illustrate a complex homeostatic interplay between IL-2, CD4(+) Th cells, FoxP3(+) CD4(+) Treg cells and autoregulatory CD8(+) T-cell memory whereby IL-2 controls the function of both Treg-cell subsets, but IL-2-potentiation of FoxP3(+) CD4(+) Treg-cell function results in the suppression of CD4(+) Th-cell activation and autoregulatory memory CD8(+) T-cell formation.

Autoantigen recognition is required for recruitment of IGRP(206-214)-autoreactive CD8+ T cells but is dispensable for tolerance.

The progression of autoimmune responses is associated with an avidity maturation process driven by preferential expansion of high avidity clonotypes at the expense of their low avidity counterparts. Central and peripheral tolerance hinder the contribution of high-avidity clonotypes targeting residues 206-214 of islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP(206-214)) during the earliest stages of autoimmune diabetes. In this study, we probe the molecular determinants and biochemical consequences of IGRP(206-214)/K(d) recognition by high-, intermediate-, and low-avidity autoreactive CD8+ T cells, and we investigate the effects of genetic IGRP(206-214) silencing on their developmental biology. We find that differences in avidity for IGRP(206-214)/K(d) map to CDR1α and are associated with quantitative differences in CD3ε proline-rich sequence exposure and Nck recruitment. Unexpectedly, we find that tolerance of high-avidity CD8+ T cells, unlike their activation and recruitment into the pancreas, is dissociated from recognition of IGRP(206-214), particularly in adult mice. This finding challenges the view that tolerance of pathogenic autoreactive T cells is invariably triggered by recognition of the peptide-MHC complex that drives their activation in the periphery, indicating the existence of mechanisms of tolerance that are capable of sensing the avidity, hence pathogenicity of autoreactive T cells without the need to rely on local autoantigen availability.

Sex differences in systemic inflammation and immune function in diet-induced obesity rodent models: A systematic review.

Understanding sex differences in immunological responses in the context of obesity is important to improve health outcomes. This systematic review aimed to investigate sex differences in systemic inflammation, immune cell phenotype, and function in diet-induced obesity (DIO) animal models. A systematic search in Medline, Embase, and CINAHL from inception to April 2023 was conducted, using a combination of the following concepts: sex, obesity, cytokines, and immune cell phenotypes/function. Forty-one publications reporting on systemic inflammation (61%), cell phenotype (44%), and/or function (7%) were included. Females had lower systemic inflammation compared with males in response to DIO intervention and a higher proportion of macrophage (M)2-like cells compared with males that had a higher proportion of M1-like in adipose tissue. Although there were no clear sex differences in immune function, high-fat DIO intervention remains an important factor in the development of immune dysfunction in both males and females, including disturbances in cytokine production, proliferation, and migration of immune cells. Yet, the mechanistic links between diet and obesity on such immune dysfunction remain unclear. Future studies should investigate the role of diet and obesity in the functionality of immune cells and employ adequate methods for a high-quality investigation of sex differences in this context.

Quantifying the importance of pMHC valency, total pMHC dose and frequency on nanoparticle therapeutic efficacy.

Nanoparticles (NPs) coated with ß-cell-specific peptide major histocompatibility complex (pMHC) class I molecules can effectively restore normoglycemia in spontaneously diabetic nonobese diabetic mice. They do so by expanding pools of cognate memory autoreactive regulatory CD8+ T cells that arise from naive low-avidity T-cell precursors to therapeutic levels. Here we develop our previously constructed mathematical model to explore the effects of compound design parameters (NP dose and pMHC valency) on therapeutic efficacy with the underlying hypothesis that the functional correlates of the therapeutic response (expansion of autoregulatory T cells and deletion of autoantigen-loaded antigen-presenting cells by these T cells) are biphasic. We show, using bifurcation analysis, that the model exhibits a 'resonance'-like behavior for a given range of NP dose in which bistability between the healthy state (possessing zero level of effector T-cell population) and autoimmune state (possessing elevated level of the same population) disappears. A heterogeneous population of model mice subjected to several treatment protocols under these new conditions is conducted to quantify both the average percentage of autoregulatory T cells in responsive and nonresponsive model mice, and the average valency-dependent minimal optimal dose needed for effective therapy. Our results reveal that a moderate increase (≥1.6-fold) in the NP-dependent expansion rate of autoregulatory T-cell population leads to a significant increase in the efficacy and the area corresponding to the effective treatment regimen, provided that NP dose ≥8 µg. We expect the model developed here to generalize to other autoimmune diseases and serve as a computational tool to understand and optimize pMHC-NP-based therapies.

Neutralizing epitopes in the membrane-proximal external region of HIV-1 gp41 are influenced by the transmembrane domain and the plasma membrane.

Failure to elicit broadly neutralizing (bNt) antibodies (Abs) against the membrane-proximal external region of HIV-1 gp41 (MPER) reflects the difficulty of mimicking its neutralization-competent structure (NCS). Here, we analyzed MPER antigenicity in the context of the plasma membrane and identified a role for the gp41 transmembrane domain (TM) in exposing the epitopes of three bNt monoclonal Abs (MAbs) (2F5, 4E10, and Z13e1). We transiently expressed DNA constructs encoding gp41 ectodomain fragments fused to either the TM of the platelet-derived growth factor receptor (PDGFR) or the gp41 TM and cytoplasmic tail domain (CT). Constructs encoding the MPER tethered to the gp41 TM followed by a 27-residue CT fragment (MPER-TM1) produced optimal MAb binding. Critical binding residues for the three Nt MAbs were identified using a panel of 24 MPER-TM1 mutants bearing single amino acid substitutions in the MPER; many were previously shown to affect MAb-mediated viral neutralization. Moreover, non-Nt mutants of MAbs 2F5 and 4E10 exhibited a reduction in binding to MPER-TM1 and yet maintained binding to synthetic MPER peptides, indicating that MPER-TM1 better approximates the MPER NCS than peptides. Replacement of the gp41 TM and CT of MPER-TM1 with the PDGFR TM reduced binding by MAb 4E10, but not 2F5, indicating that the gp41 TM plays a pivotal role in orienting the 4E10 epitope, and more globally, in affecting MPER exposure.

In situ recognition of autoantigen as an essential gatekeeper in autoimmune CD8+ T cell inflammation.

A current paradigm states that non-antigen-specific inflammatory cues attract noncognate, bystander T cell specificities to sites of infection and autoimmune inflammation. Here we show that cues emanating from a tissue undergoing spontaneous autoimmune inflammation cannot recruit naive or activated bystander T cell specificities in the absence of local expression of cognate antigen. We monitored the recruitment of CD8(+) T cells specific for the prevalent diabetogenic epitope islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP)(206-214) in gene-targeted nonobese diabetic (NOD) mice expressing a T cell "invisible" IGRP(206-214) sequence. These mice developed islet inflammation and diabetes with normal incidence and kinetics, but their inflammatory lesions could recruit neither naive (endogenous or exogenous) nor ex vivo-activated IGRP(206-214)-reactive CD8(+) T cells. Conversely, IGRP(206-214)-reactive, but not nonautoreactive CD8(+) T cells rapidly homed to and accumulated in the inflamed islets of wild-type NOD mice. Our results indicate that CD8(+) T cell recruitment to a site of autoimmune inflammation results from an active process that is strictly dependent on local display of cognate pMHC and suggest that CD8(+) T cells contained in extralymphoid autoimmune lesions are largely autoreactive.

Maternal provisions in type 1 diabetes: Evidence for both protective & pathogenic potential.

Maternal influences on the immune health and development of an infant begin in utero and continue well into the postnatal period, shaping and educating the child's maturing immune system. Two maternal provisions include early microbial colonizers to initiate microbiota establishment and the transfer of antibodies from mother to baby. Maternal antibodies are a result of a lifetime of antigenic experience, reflecting the infection history, health and environmental exposure of the mother. These same factors are strong influencers of the microbiota, inexorably linking the two. Together, these provisions help to educate the developing neonatal immune system and shape lymphocyte repertoires, establishing a role for external environmental influences even before birth. In the context of autoimmunity, the transfer of maternal autoantibodies has the potential to be harmful for the child, sometimes targeting tissues and cells with devastating consequences. Curiously, this does not seem to apply to maternal autoantibody transfer in type 1 diabetes (T1D). Moreover, despite the rising prevalence of the disease, little research has been conducted on the effects of maternal dysbiosis or antibody transfer from an affected mother to her offspring and thus their relevance to disease development in the offspring remains unclear. This review seeks to provide a thorough evaluation of the role of maternal microorganisms and antibodies within the context of T1D, exploring both their pathogenic and protective potential. Although a definitive understanding of their significance in infant T1D development remains elusive at present, we endeavor to present what has been learned with the goal of spurring further interest in this important and intriguing question.

Corrigendum: The interplay of obesity, dyslipidemia and immune dysfunction: a brief overview on pathophysiology, animal models, and nutritional modulation.

[This corrects the article DOI: 10.3389/fnut.2022.840209.].