Assuntos
Aminofenóis , Benzodioxóis , Fibrose Cística , Citocinas , Indóis , Células T Invariantes Associadas à Mucosa , Pirazóis , Quinolonas , Humanos , Fibrose Cística/tratamento farmacológico , Aminofenóis/uso terapêutico , Criança , Benzodioxóis/uso terapêutico , Indóis/uso terapêutico , Quinolonas/uso terapêutico , Pirazóis/uso terapêutico , Masculino , Feminino , Células T Invariantes Associadas à Mucosa/imunologia , Células T Invariantes Associadas à Mucosa/efeitos dos fármacos , Citocinas/metabolismo , Piridinas/uso terapêutico , Adolescente , Combinação de Medicamentos , Quinolinas/uso terapêutico , Pirróis/uso terapêutico , Pré-Escolar , PirrolidinasRESUMO
Mucosal-associated invariant T (MAIT) cells are restricted by MR1 and are known to protect against bacterial and viral infections. Our understanding of the role of MAIT cells in parasitic infections, such as visceral leishmaniasis (VL) caused by protozoan parasites of Leishmania donovani, is limited. This study showed that in response to L. infantum, human peripheral blood MAIT cells from children with leishmaniasis produced TNF and IFN-γ in an MR1-dependent manner. The overall frequency of MAIT cells was inversely correlated with alanine aminotransferase levels, a specific marker of liver damage strongly associated with severe hepatic involvement in VL. In addition, there was a positive correlation between total protein levels and the frequency of IL-17A+ CD8+ MAIT cells, whereby reduced total protein levels are a marker of liver and kidney damage. Furthermore, the frequencies of IFN-γ+ and IL-10+ MAIT cells were inversely correlated with hemoglobin levels, a marker of severe anemia. In asymptomatic individuals and VL patients after treatment, MAIT cells also produced IL-17A, a cytokine signature associated with resistance to visceral leishmaniasis, suggesting that MAIT cells play important role in protecting against VL. In summary, these results broaden our understanding of MAIT-cell immunity to include protection against parasitic infections, with implications for MAIT-cell-based therapeutics and vaccines. At last, this study paves the way for the investigation of putative MAIT cell antigens that could exist in the context of Leishmania infection.
Assuntos
Leishmaniose Visceral , Células T Invariantes Associadas à Mucosa , Alanina Transaminase , Criança , Citocinas , Hemoglobinas , Humanos , Interleucina-10 , Interleucina-17RESUMO
Recently, cell-mediated immune response in malignant neoplasms has become the focus in immunotherapy against cancer. However, in leukemia, most studies on the cytotoxic potential of T cells have concentrated only on T cells that recognize peptide antigens (Ag) presented by polymorphic molecules of the major histocompatibility complex (MHC). This ignores the great potential of unconventional T cell populations, which include gamma-delta T cells (γδ), natural killer T cells (NKT), and mucosal-associated invariant T cells (MAIT). Collectively, these T cell populations can recognize lipid antigens, specially modified peptides and small molecule metabolites, in addition to having several other advantages, which can provide more effective applications in cancer immunotherapy. In recent years, these cell populations have been associated with a repertoire of anti- or protumor responses and play important roles in the dynamics of solid tumors and hematological malignancies, thus, encouraging the development of new investigations in the area. This review focuses on the current knowledge regarding the role of unconventional T cell populations in the antitumor immune response in leukemia and discusses why further studies on the immunotherapeutic potential of these cells are needed.
Assuntos
Imunoterapia Adotiva/métodos , Linfócitos Intraepiteliais/imunologia , Leucemia/terapia , Células T Invariantes Associadas à Mucosa/imunologia , Células T Matadoras Naturais/imunologia , Ensaios Clínicos Fase I como Assunto , Humanos , Leucemia/imunologia , Receptores de Antígenos Quiméricos/imunologiaRESUMO
Asthma is a chronic immunological disease affecting all age groups, but often starting in childhood. Although it has long been ascribed to a single pathology, recent studies have highlighted its heterogeneity due to the potential involvement of various pathogenic mechanisms. Here, we present our current understanding of the role of innate-like T (ILT) cells in asthma pathogenesis. These cells constitute a specific family mainly comprising γδT, invariant natural killer (iNKT) and mucosal-associated invariant (MAIT) T cells. They all share the ability to massively secrete a wide range of cytokines in a T-cell receptor (TCR)-dependent or -independent manner. ILT cells are prevalent in mucosal tissues, including airways, where their innate and adaptive immune functions consist primarily in protecting tissue integrity. However, ILT cells may also have detrimental effects leading to asthma symptoms. The immune mechanisms through which this pathogenic effect occurs will be discussed in this overview.
Assuntos
Asma/etiologia , Asma/metabolismo , Suscetibilidade a Doenças , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Animais , Asma/patologia , Citocinas/metabolismo , Modelos Animais de Doenças , Humanos , Mediadores da Inflamação/metabolismo , Células T Invariantes Associadas à Mucosa/imunologia , Células T Invariantes Associadas à Mucosa/metabolismo , Células T Matadoras Naturais/imunologia , Células T Matadoras Naturais/metabolismo , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Subpopulações de Linfócitos T/patologiaRESUMO
Objective: To investigate the frequency, phenotype, function, and longitudinal repertoire of mucosal-associated invariant T (MAIT) cells in relapsing remitting multiple sclerosis (RRMS) and primary progressive multiple sclerosis (PPMS) patients. Methods: Forty-five RRMS patients in remission, 20 RRMS patients experiencing exacerbations, 15 PPMS patients, and 30 healthy controls (HCs) were included in the study. MAIT cells were identified phenotypically as CD3+ TCRγδ- Vα7.2 + CD161high. In 15 patients, MAIT cell number and MRI lesions were evaluated every 6 months, for 36 months. MAIT cell TCRVß repertoire was defined using single-cell cloning and mRNA sequencing. Results: Circulating MAIT cells were significantly reduced in both RRMS and PPMS patients, particularly during exacerbations, compared to healthy subjects. This decrease was accompanied by pro-inflammatory cytokine production (TNF-α, IFN-γ, IL-17, and GM-CSF). Three months post-exacerbation, peripheral blood MAIT cell percentages increased significantly along with clinical recovery. Likewise, we observed inverse correlation between MRI lesions and peripheral blood MAIT cell numbers. In paired samples, MAIT cell percentage was significantly higher in CSF than in peripheral blood, suggesting MAIT cell migration through the blood-brain barrier. Finally, MAIT cells showed limited TCRVß repertoires, in both CSF and peripheral blood, which remained stable over time. Conclusions: MAIT cell levels correlated with MS course both clinically and radiologically, showing marked and sustained oligoclonality. These findings may contribute to a better understanding of pathophysiological phenomena underlying the course of MS, and discovery of MAIT cell inhibitors could pave the way for the development of new therapeutic strategies.
Assuntos
Células T Invariantes Associadas à Mucosa/imunologia , Esclerose Múltipla Crônica Progressiva/imunologia , Esclerose Múltipla Recidivante-Remitente/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/imunologiaRESUMO
It has been almost two decades since the discovery of mucosal-associated invariant T (MAIT)-cells. Several advances in the field have been made such as the discovery of the antimicrobial activity of MAIT-cells, the abundance of these cells in human mucosa and in liver and the discovery of ligands able to bind MR1 and activate MAIT-cells. MAIT-cells are a unique subset of innate-like T-cells that express a canonical T-cell receptor with the alpha chain containing hAV7S2 and AJ33 in humans (TCRVα7.2Jα33) and respond to bacterial/fungus vitamin B2 metabolites by an MR1-dependent pathway. Indirect activation is also observed during chronic viral infections by and IL-12/IL-18 pathway. In this review, the mechanisms of activation, the timeline of MAIT-cell development in humans as well as their role in human infection are discussed. On the whole, we believe that harnessing the anti-microbial ability of MAIT-cells could contribute for the design of potent immunotherapies and vaccines against "hard-to-kill" infectious agents that remain as public health threats worldwide.