Interleukin-17-producing γδ T (γδ17) cells play a central role in protective and pathogenic immune responses. However, the tissue-specific mechanisms that control the activation of these innate ...lymphocytes are not known. Here, we demonstrate that CD109, a glycosylphosphatidylinositol (GPI)-anchored protein highly expressed by keratinocytes, is an important regulator of skin homeostasis and γδ17 cell activation. Genetic deletion of CD109 results in spontaneous epidermal hyperplasia, aberrant accumulation of dermal-derived γδ17 cells, and enhanced susceptibility to psoriasiform inflammation. In this context, γδ17 activation requires interleukin (IL)-23 signals and is reversed by transient depletion of the skin microbiota. Mechanistically, CD109 restrains γδ17 cell activation in a cell-extrinsic manner by fortifying skin barrier integrity. Collectively, our data provide insight into the regulation of the skin IL-23/IL-17 immune axis and how homeostasis is maintained at this important barrier site.
Display omitted
•CD109 is a negative regulator of the cutaneous IL-23/IL-17 immune axis•Deletion of CD109 amplifies IL-17 production by skin γδ T cells•CD109 enforces skin barrier integrity and reactivity to commensal microbiota
Zhang et al. demonstrate that CD109 acts in a skin-specific and cell-extrinsic manner to regulate interleukin (IL)-17 production by cutaneous γδ T cells. Genetic loss of CD109 results in spontaneous skin inflammation and an enhanced susceptibility to psoriasiform inflammation, a phenotype that can be reversed with topical application of antibiotics.
The AHR target genes are differentially regulated by PAMPs, in human monocytes and monocyte‐derived macrophages.
The aryl hydrocarbon receptor (AHR) is a ligand‐activated transcription factor that ...triggers a broad response, which includes the regulation of proinflammatory cytokine production by monocytes and macrophages. AHR is negatively regulated by a set of genes that it transcriptionally activates, including the AHR repressor (Ahrr) and the cytochrome P450 1 (Cyp1) family, which are critical for preventing exacerbated AHR activity. An imbalance in these regulatory mechanisms has been shown to cause severe defects in lymphoid cells. Therefore, we wanted to assess how AHR activation is regulated in monocytes and macrophages in the context of innate immune responses induced by pathogen‐associated molecular patterns (PAMPs). We found that concomitant stimulation of primary human monocytes with PAMPs and the AHR agonist 6‐formylindolo(3,2‐b)carbazole (FICZ) led to a selective dose‐dependent inhibition of Cyp1 family members induction. Two other AHR‐dependent genes Ahrr and NADPH quinone dehydrogenase 1 (Nqo1) were not affected under these conditions, suggesting a split in the AHR regulation by PAMPs. This down‐regulation of Cyp1 family members did not require de novo protein production nor signaling through p38, ERK, or PI3K‐Akt‐mammalian target of rapamycin (mTOR) pathways. Furthermore, such a split regulation of the AHR response was more apparent in GM‐CSF‐derived macrophages, a finding corroborated at the functional level by decreased CYP1 activity and decreased proinflammatory cytokine production in response to FICZ and LPS. Collectively, our findings identify a role for pattern recognition receptor (PRR) signaling in regulating the AHR response through selective down‐regulation of Cyp1 expression in human monocytes and macrophages.
Interleukin-17 (IL-17)-producing γδ (γδ17) T cells are innate-like lymphocytes that contribute to protective anti-microbial responses but are also implicated in pathogenic inflammation at barrier ...sites. Understanding tissue-specific signals that regulate this subset is important to boost host defense mechanisms, but also to mitigate immunopathology. Here, we demonstrate that prostaglandin E2 (PGE2), a cyclooxygenase-dependent member of the eicosanoid family, directly enhances cytokine production by circulating and tissue-specific γδ17 T cells in vitro. Gain- and loss-of-function in vivo approaches further reveal that although provision of PGE2 amplifies psoriasiform inflammation, ablation of host mPGES1-dependent PGE2 synthesis is dispensable for cutaneous γδ17 T cell activation. By contrast, loss of endogenous PGE2 production or depletion of the gut microbiota compromises intestinal γδ17 T cell responses and increases disease severity during experimental colitis. Together, our results demonstrate how a lipid mediator can synergize with tissue-specific signals to enhance innate lymphocyte production of IL-17 during barrier inflammation.
Display omitted
•PGE2 potently enhances IL-17 production by thymically imprinted γδ17 T cells•PGE2 supplementation amplifies IL-17-dependent psoriasiform inflammation•Loss of mPGES1-dependent PGE2 compromises intestinal γδ17 T cell responses•γδ17 T cell activation during DSS requires commensal gut microbiota
Polese and Thurairajah et al. demonstrate that the lipid mediator prostaglandin E2 enhances IL-17 secretion by murine γδ T cells and amplifies psoriasiform inflammation while limiting colitis severity. Their results suggest a tissue-specific role for PGE2 production in regulating γδ17 T cell responses and pathological inflammation at barrier sites.
A number of food allergies (eg, fish, shellfish, and nuts) are lifelong, without any disease-transforming therapies, and unclear in their underlying immunology. Clinical manifestations of food ...allergy are largely mediated by IgE. Although persistent IgE titers have been attributed conventionally to long-lived IgE+ plasma cells (PCs), this has not been directly and comprehensively tested.
We sought to evaluate mechanisms underlying persistent IgE and allergic responses to food allergens.
We used a model of peanut allergy and anaphylaxis, various knockout mice, adoptive transfer experiments, and in vitro assays to identify mechanisms underlying persistent IgE humoral immunity over almost the entire lifespan of the mouse (18-20 months).
Contrary to conventional paradigms, our data show that clinically relevant lifelong IgE titers are not sustained by long-lived IgE+ PCs. Instead, lifelong reactivity is conferred by allergen-specific long-lived memory B cells that replenish the IgE+ PC compartment. B-cell reactivation requires allergen re-exposure and IL-4 production by CD4 T cells. We define the half-lives of antigen-specific germinal centers (23.3 days), IgE+ and IgG1+ PCs (60 and 234.4 days, respectively), and clinically relevant cell-bound IgE (67.3 days).
These findings can explain lifelong food allergies observed in human subjects as the consequence of allergen exposures that recurrently activate memory B cells and identify these as a therapeutic target with disease-transforming potential.
Display omitted
Mouse invariant natural killer T cells (iNKT cells) provide cognate and noncognate help for lipid and protein-specific B cells, respectively. However, the long-term outcome for B cells after cognate ...help is provided by iNKT cells is unknown at present. Here we found that cognate iNKT cell help resulted in a B cell differentiation program characterized by extrafollicular plasmablasts, germinal-center formation, affinity maturation and a robust primary immunoglobulin G (IgG) antibody response that was uniquely dependent on iNKT cell-derived interleukin 21 (IL-21). However, cognate help from iNKT cells did not generate an enhanced humoral memory response. Thus, cognate iNKT cell help for lipid-specific B cells induces a unique signature that is a hybrid of classic T cell-dependent and T cell-independent type 2 B cell responses.
Enteric helminths form intimate physical connections with the intestinal epithelium, yet their ability to directly alter epithelial stem cell fate has not been resolved. Here we demonstrate that ...infection of mice with the parasite Heligmosomoides polygyrus bakeri (Hpb) reprograms the intestinal epithelium into a fetal-like state marked by the emergence of Clusterin-expressing revival stem cells (revSCs). Organoid-based studies using parasite-derived excretory-secretory products reveal that Hpb-mediated revSC generation occurs independently of host-derived immune signals and inhibits type 2 cytokine-driven differentiation of secretory epithelial lineages that promote their expulsion. Reciprocally, type 2 cytokine signals limit revSC differentiation and, consequently, Hpb fitness, indicating that helminths compete with their host for control of the intestinal stem cell compartment to promote continuation of their life cycle.
In schistosomiasis patients, parasite eggs trapped in hepatic sinusoids become foci for CD4+ T cell-orchestrated granulomatous cellular infiltrates. Since the immune response is unable to clear the ...infection, the liver is subjected to ongoing cycles of focal inflammation and healing that lead to vascular obstruction and tissue fibrosis. This is mitigated by regulatory mechanisms that develop over time and which minimize the inflammatory response to newly deposited eggs. Exploring changes in the hepatic inflammatory infiltrate over time in infected mice, we found an accumulation of schistosome egg antigen-specific IgG1-secreting plasma cells during chronic infection. This population was significantly diminished by blockade of the receptor for IL-10, a cytokine implicated in plasma cell development. Strikingly, IL-10R blockade precipitated the development of portal hypertension and the accumulation of parasite eggs in the lungs and heart. This did not reflect more aggressive Th2 cell responsiveness, increased hepatic fibrosis, or the emergence of Th1 or Th17 responses. Rather, a role for antibody in the prevention of severe disease was suggested by the finding that pulmonary involvement was also apparent in mice unable to secrete class switched antibody. A major effect of anti-IL-10R treatment was the loss of a myeloid population that stained positively for surface IgG1, and which exhibited characteristics of regulatory/anti-inflammatory macrophages. This finding suggests that antibody may promote protective effects within the liver through local interactions with macrophages. In summary, our data describe a role for IL-10-dependent B cell responses in the regulation of tissue damage during a chronic helminth infection.
Expression of the signaling lymphocytic activation molecule (SLAM)-associated protein (SAP) is critical for the germinal center (GC) reaction and T cell-dependent antibody production. However, when ...SAP is expressed normally, the role of the associated SLAM family receptors (SFRs) in these processes is nebulous. Herein, we established that in the presence of SAP, SFRs suppressed the expansion of the GC reaction but facilitated the generation of antigen-specific B cells and antibodies. SFRs favored the generation of antigen-reactive B cells and antibodies by boosting expression of pro-survival effectors, such as the B cell antigen receptor (BCR) and Bcl-2, in activated GC B cells. The effects of SFRs on the GC reaction and T cell-dependent antibody production necessitated expression of multiple SFRs, both in T cells and in B cells. Hence, while in the presence of SAP, SFRs inhibit the GC reaction, they are critical for the induction of T cell-mediated humoral immunity by enhancing expression of pro-survival effectors in GC B cells.
Pathogen-specific Ab production following infection with the gut-dwelling roundworm Heligmosomoides polygyrus is critical for protective immunity against reinfection. However, the factors required ...for productive T cell-B cell interactions in the context of a type 2-dominated immune response are not well defined. In the present study, we identify IL-21R signaling as a critical factor in driving pathogen-specific plasma cell differentiation and protective immunity against H. polygyrus in mice. We show that B cells require direct IL-21R signals to differentiate into CD138(+) plasma cells. In contrast, IL-21R signaling is dispensable for germinal center formation, isotype class switching, and Th2 and T follicular helper cell differentiation. Our studies demonstrate a selective role for IL-21 in plasma cell differentiation in the context of protective antiparasitic type 2 immunity.
Zika virus (ZIKV) is a mosquito-borne pathogen that recently caused a series of increasingly severe outbreaks. We previously demonstrated that, compared with a pre-epidemic isolate (ZIKV
), a ...Brazilian ZIKV isolate (ZIKV
) possesses a novel capacity to suppress host immunity, resulting in delayed viral clearance. However, whether ZIKV
modulates CD4 T cell responses remains unknown. In this study, we show that, in comparison with ZIKV
infection, CD4 T cells are less polarized to the Th1 subtype following ZIKV
challenge in mice. In contrast, we observed an enhanced accumulation of T follicular helper cells 10, 14, and 21 d postinfection with ZIKV
This response correlated with an enhanced germinal center B cell response and robust production of higher avidity-neutralizing Abs following ZIKV
infection. Taken together, our data suggest that contemporary ZIKV strains have evolved to differentially induce CD4 T cell, B cell, and Ab responses and this could provide a model to further define the signals required for T follicular helper cell development.
PDF
