MAIT cells are an unconventional T cell population that can be activated through both TCR-dependent and TCR-independent mechanisms. Here, we examined the impact of combinations of TCR-dependent and ...TCR-independent signals in human CD8+ MAIT cells. TCR-independent activation of these MAIT cells from blood and gut was maximized by extending the panel of cytokines to include TNF-superfamily member TL1A. RNA-seq experiments revealed that TCR-dependent and TCR-independent signals drive MAIT cells to exert overlapping and specific effector functions, affecting both host defense and tissue homeostasis. Although TCR triggering alone is insufficient to drive sustained activation, TCR-triggered MAIT cells showed specific enrichment of tissue-repair functions at the gene and protein levels and in in vitro assays. Altogether, these data indicate the blend of TCR-dependent and TCR-independent signaling to CD8+ MAIT cells may play a role in controlling the balance between healthy and pathological processes of tissue inflammation and repair.
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•Activation of human MAIT cells is TCR-dependent or TCR-independent and enhanced by TL1A•TCR-dependent and TCR-independent triggering induces distinct transcriptional responses•TCR-dependent triggering of MAIT cells induces a tissue-repair program•Data integration with in vivo studies in mice indicates a shared transcriptome
Leng et al. explore the consequences of activation of human MAIT cells via their TCR and/or cytokines, including the gut-associated TNF-superfamily member TL1A. TCR triggering reveals a transcriptional program linked to tissue-repair functions seen in vivo, consistent with a homeostatic role for these cells in epithelia.
Significance Methotrexate (MTX) is the first-line therapy for rheumatoid arthritis (RA). However, about 40% of patients are resistant to MTX. Furthermore, MTX resistance is only apparent after a ...prolonged continuous MTX treatment (>3 mo), by which time the disease of the nonresponders would have aggravated. Thus, there is a considerable unmet need for a biomarker to select MTX-resistant patients and place them immediately on alternative therapy. We found here that the low density of CD39 on peripheral regulatory T cells in RA patients is a rapid, convenient, and reliable ( P < 0.01) biomarker for MTX resistance. Our findings also provide previously unrecognized information on aspects of immune regulation in RA and the mechanism of action of MTX.
Rheumatoid arthritis (RA) is an inflammatory autoimmune disease characterized by joint destruction and severe morbidity. Methotrexate (MTX) is the standard first-line therapy of RA. However, about 40% of RA patients are unresponsive to MTX treatment. Regulatory T cells (Tregs, CD4 ⁺CD25 ⁺FoxP3 ⁺) are thought to play an important role in attenuating RA. To investigate the role of Tregs in MTX resistance, we recruited 122 RA patients (53 responsive, R-MTX; 69 unresponsive, UR-MTX) and 33 healthy controls. Three months after MTX treatment, R-MTX but not UR-MTX showed higher frequency of peripheral blood CD39 ⁺CD4 ⁺CD25 ⁺FoxP3 ⁺ Tregs than the healthy controls. Tregs produce adenosine (ADO) through ATP degradation by sequential actions of two cell surface ectonucleotidases: CD39 and CD73. Tregs from UR-MTX expressed a lower density of CD39, produced less ADO, and had reduced suppressive activity than Tregs from R-MTX. In a prospective study, before MTX treatment, UR-MTX expressed a lower density of CD39 on Tregs than those of R-MTX or control ( P < 0.01). In a murine model of arthritis, CD39 blockade reversed the antiarthritic effects of MTX treatment. Our results demonstrate that MTX unresponsiveness in RA is associated with low expression of CD39 on Tregs and the decreased suppressive activity of these cells through reduced ADO production. Our findings thus provide hitherto unrecognized mechanism of immune regulation in RA and on mode of action of MTX. Furthermore, our data suggest that low expression of CD39 on Tregs could be a noninvasive biomarker for identifying MTX-resistant RA patients.
Abstract
The aryl hydrocarbon receptor (AHR) is a transcription factor activated by ligand highly expressed on T
H
17 cells, and AHR-deficient CD4
+
T cells have impaired production of IL-17A and ...IL-22. Although AHR activation can exacerbate in vivo T
H
17 cell-mediated autoimmunity, accumulating data indicate that AHR is a nonpathogenic T
H
17 marker. Thus it remains unclear how AHR activation is regulated and impacts on the generation of T
H
17 subsets. Here we demonstrated that AHR pathway is activated during in vitro pathogenic T
H
17 polarization, but it is quickly downregulated. Under these conditions, additional AHR activation promoted IL-22 but not IL-17A. Interestingly, AHR high sustained expression and IL-17A promotion were only achieved when TGFβ1 was present in the culture. In addition to the effect on AHR regulation, TGFβ1 presented a dual role by simultaneously suppressing the T
H
17 pathogenic phenotype acquisition. This latter effect was independent of AHR stimulation, since its activation did not confer a T
H
17 anti-inflammatory profile and
Ahr
−
/−
cells did not upregulate any T
H
17 pathogenic marker. Through the use of EAE model, we demonstrated that AHR is still functional in encephalitogenic CD4
+
T cells and the adoptive transfer of
Ahr
−
/−
T
H
17 cells to recipient mice resulted in milder EAE development when compared to their WT counterparts. Altogether, our data demonstrated that although AHR is highly expressed on in vitro-generated nonpathogenic T
H
17 cells, its ligation does not shift T
H
17 cells to an anti-inflammatory phenotype. Further studies investigating the role of AHR beyond T
H
17 differentiation may provide a useful understanding of the physiopathology of autoimmune diseases.
Current inflammatory bowel disease (IBD) therapies are ineffective in a high proportion of patients. Combining bulk and single-cell transcriptomics, quantitative histopathology and in situ ...localization across three cohorts of patients with IBD (total n = 376), we identify coexpressed gene modules within the heterogeneous tissular inflammatory response in IBD that map to distinct histopathological and cellular features (pathotypes). One of these pathotypes is defined by high neutrophil infiltration, activation of fibroblasts and vascular remodeling at sites of deep ulceration. Activated fibroblasts in the ulcer bed display neutrophil-chemoattractant properties that are IL-1R, but not TNF, dependent. Pathotype-associated neutrophil and fibroblast signatures are increased in nonresponders to several therapies across four independent cohorts (total n = 343). The identification of distinct, localized, tissular pathotypes will aid precision targeting of current therapeutics and provides a biological rationale for IL-1 signaling blockade in ulcerating disease.
Sepsis results in elevated adenosine in circulation. Extracellular adenosine triggers immunosuppressive signaling via the A2a receptor (A2aR). Sepsis survivors develop persistent immunosuppression ...with increased risk of recurrent infections. We utilized the cecal ligation and puncture (CLP) model of sepsis and subsequent infection to assess the role of adenosine in post-sepsis immune suppression. A2aR-deficient mice showed improved resistance to post-sepsis infections. Sepsis expanded a subset of CD39hi B cells and elevated extracellular adenosine, which was absent in mice lacking CD39-expressing B cells. Sepsis-surviving B cell-deficient mice were more resistant to secondary infections. Mechanistically, metabolic reprogramming of septic B cells increased production of ATP, which was converted into adenosine by CD39 on plasmablasts. Adenosine signaling via A2aR impaired macrophage bactericidal activity and enhanced interleukin-10 production. Septic individuals exhibited expanded CD39hi plasmablasts and adenosine accumulation. Our study reveals CD39hi plasmablasts and adenosine as important drivers of sepsis-induced immunosuppression with relevance in human disease.
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•Sepsis induces expansion of an immune-suppressive CD39-expressing B cell population•Septic B cells have metabolic reprogramming supporting their suppressive activity•Adenosine derived from CD39+ B cells impairs macrophage bacterial killing•Adenosine signaling via A2aR promotes macrophage production of suppressive IL-10
Sepsis causes immunosuppression and increased susceptibility to infection by unknown means. Nascimento et al. show sepsis-induced expansion of a CD39hi plasmablast population that elevated circulating adenosine. Adenosine signaling in macrophages suppressed microbial killing and promoted IL-10 production. This work highlights CD39hi plasmablasts and adenosine as important drivers of sepsis-induced immunosuppression.
Is the BCG Vaccine Safe for Undernourished Individuals? Ishikawa, Larissa Lumi Watanabe; da Rosa, Larissa Camargo; França, Thais Graziela Donegá ...
Clinical & developmental immunology,
01/2012, Letnik:
2012
Journal Article
Recenzirano
Odprti dostop
Cellular immunity is critical for protection against tuberculosis, but its integrity is compromised during undernutrition. The present study was designed to evaluate if the attenuated mycobacterium ...BCG is a safe vaccine for undernourished individuals. An experimental model of undernutrition was established by subjecting BALB/c mice to dietary restriction. These animals received 70% of the amount of food consumed by the healthy control group and exhibited physiological alterations compatible with malnutrition, including body weight loss, reduced levels of triglycerides and glucose, and reduced lymphocyte numbers. Undernourished mice were immunized with BCG, and the mycobacterial loads in lymph nodes, spleen, liver, lungs, and thymus were determined. A much higher proportion of undernourished mice exhibited bacterial dissemination to the lymph nodes, spleen and liver. In addition, only undernourished animals had bacteria in the lungs and thymus. Concomitant with higher mycobacterial loads and more widespread BCG dissemination in undernourished mice, production of TNF-α, IFN-γ, and IL-10 was also diminished in these mice. Taken together, these results indicate that BCG infection is more severe in undernourished mice. Whether a similar phenomenon exists in undernourished children or not remains to be thoroughly investigated.
•Immunization with citrullinated human fibrinogen induces ACPA antibody production.•Joint injection of human fibrinogen causes arthritis in previously immunized mice.•Human fibrinogen-induced ...arthritis depends on IL-17/IL-23 immune axis response.
Rheumatoid arthritis (RA) is an autoimmune disease that causes joint destruction. Although its etiology remains unknown, citrullinated proteins have been considered as an auto-antigen able to trigger an inflammatory response in RA. Herein, we modified the classical antigen-induced arthritis (AIA) model by using citrullinated human plasma fibrinogen (hFIB) as an immunogen to investigate the mechanism of inflammation-driven joint damage by citrullinated hFIB in C57BL/6 mice. We found that hFIB-immunized mice showed high serum levels of anti-citrullinated peptides antibodies (ACPAs). Moreover, hFIB immunized mice showed increased mechanical hyperalgesia, massive leukocyte infiltration, high levels of inflammatory mediators, and progressive joint damage after the intra-articular challenge with citrullinated hFIB. Interestingly, hFIB-induced arthritis was dependent on IL-23/IL-17 immune axis-mediated inflammatory responses since leukocyte infiltration and mechanical hyperalgesia were abrogated in Il17ra−/− and Il23a−/− mice. Thus, we have characterized a novel model of experimental arthritis suitable to investigate the contribution of ACPAs and Th17 cell-mediated immune response in the pathogenesis of RA.
The aryl hydrocarbon receptor (AHR) is a transcription factor activated by ligand highly expressed on T
17 cells, and AHR-deficient CD4
T cells have impaired production of IL-17A and IL-22. Although ...AHR activation can exacerbate in vivo T
17 cell-mediated autoimmunity, accumulating data indicate that AHR is a nonpathogenic T
17 marker. Thus it remains unclear how AHR activation is regulated and impacts on the generation of T
17 subsets. Here we demonstrated that AHR pathway is activated during in vitro pathogenic T
17 polarization, but it is quickly downregulated. Under these conditions, additional AHR activation promoted IL-22 but not IL-17A. Interestingly, AHR high sustained expression and IL-17A promotion were only achieved when TGFβ1 was present in the culture. In addition to the effect on AHR regulation, TGFβ1 presented a dual role by simultaneously suppressing the T
17 pathogenic phenotype acquisition. This latter effect was independent of AHR stimulation, since its activation did not confer a T
17 anti-inflammatory profile and Ahr
cells did not upregulate any T
17 pathogenic marker. Through the use of EAE model, we demonstrated that AHR is still functional in encephalitogenic CD4
T cells and the adoptive transfer of Ahr
T
17 cells to recipient mice resulted in milder EAE development when compared to their WT counterparts. Altogether, our data demonstrated that although AHR is highly expressed on in vitro-generated nonpathogenic T
17 cells, its ligation does not shift T
17 cells to an anti-inflammatory phenotype. Further studies investigating the role of AHR beyond T
17 differentiation may provide a useful understanding of the physiopathology of autoimmune diseases.
•Recovery from S. venezuelensis infection is associated with Th2 polarized response.•Contact with S. venezuelensis contributed to prevent insulitis in MLD-STZ diabetes.•Protection associated with S. ...venezuelensis was linked to IL-5 and IL-10 production.
Epidemiological and experimental studies support the idea that helminth infections can induce a protective effect against the development of autoimmune and allergic diseases. In this study we characterized the immune response induced by Strongyloides venezuelensis infection in C57BL/6 mice and then evaluated the effect of a previous contact with this helminth in the outcome of type 1 diabetes. Animals were initially infected with 2000 L3 larvae from S. venezuelensis and euthanized 22days later. An acute phase, identified by a high amount of eggs per gram of feces, was established between days 7 and 9 post-infection. Recovery from infection was associated with a Th2 polarized response characterized by a significant level of serum IgG1 specific antibodies and also a significant production of IL-5 and IL-10 by spleen cells stimulated with S. venezuelensis soluble antigen. Immunization with soluble S. venezuelensis antigen associated with complete Freund’s adjuvant followed by infection with S. venezuelensis protected mice from diabetes development induced by streptozotocin. Protection was characterized by a higher body weight gain, lower glycemic levels, much less severe insulitis and preserved insulin production. Together, these results indicate that S. venezuelensis contributed to protect C57BL/6 mice against experimental diabetes induced by streptozotocin.
COVID-19 was initially characterized as a disease primarily of the lungs, but it is becoming increasingly clear that the SARS-CoV2 virus is able to infect many organs and cause a broad pathological ...response. The primary infection site is likely to be a mucosal surface, mainly the lungs or the intestine, where epithelial cells can be infected with virus. Although it is clear that virus within the lungs can cause severe pathology, driven by an exaggerated immune response, infection within the intestine generally seems to cause minor or no symptoms. In this review, we compare the disease processes between the lungs and gastrointestinal tract, and what might drive these different responses. As the microbiome is a key part of mucosal barrier sites, we also consider the effect that microbial species may play on infection and the subsequent immune responses. Because of difficulties obtaining tissue samples, there are currently few studies focused on the local mucosal response rather than the systemic response, but understanding the local immune response will become increasingly important for understanding the mechanisms of disease in order to develop better treatments.
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