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1.
Nat Commun ; 10(1): 2498, 2019 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-31175312

RESUMO

Allogeneic mesenchymal stem cells (MSCs) exhibit immunoregulatory function in human autoimmune diseases such as systemic lupus erythematosus (SLE), but the underlying mechanisms remain incompletely understood. Here we show that the number of peripheral tolerogenic CD1c+ dendritic cells (DCs) and the levels of serum FLT3L are significantly decreased in SLE patients especially with lupus nephritis, compared to healthy controls. Transplantation of allogeneic umbilical cord-derived MSCs (UC-MSCs) significantly up-regulates peripheral blood CD1c+DCs and serum FLT3L. Mechanistically, UC-MSCs express FLT3L that binds to FLT3 on CD1c+DCs to promote the proliferation and inhibit the apoptosis of tolerogenic CD1c+DCs. Conversely, reduction of FLT3L with small interfering RNA in MSCs abolishes the up-regulation of tolerogenic CD1c+DCs in lupus patients treated with MSCs. Interferon-γ induces FLT3L expression in UC-MSCs through JAK/STAT signaling pathway. Thus, allogeneic MSCs might suppress inflammation in lupus through up-regulating tolerogenic DCs.


Assuntos
Antígenos CD1/imunologia , Células Dendríticas/imunologia , Glicoproteínas/imunologia , Tolerância Imunológica/imunologia , Lúpus Eritematoso Sistêmico/terapia , Proteínas de Membrana/imunologia , Transplante de Células-Tronco Mesenquimais , Adulto , Antígenos CD1/metabolismo , Estudos de Casos e Controles , Células Dendríticas/metabolismo , Feminino , Glicoproteínas/metabolismo , Humanos , Interferon gama/farmacologia , Janus Quinases/efeitos dos fármacos , Janus Quinases/metabolismo , Lúpus Eritematoso Sistêmico/imunologia , Nefrite Lúpica/imunologia , Nefrite Lúpica/terapia , Masculino , Proteínas de Membrana/metabolismo , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismo , Pessoa de Meia-Idade , Fatores de Transcrição STAT/efeitos dos fármacos , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transplante Homólogo , Adulto Jovem
2.
PLoS Pathog ; 15(6): e1007840, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31173604

RESUMO

BLyS/BAFF is recognized for its role in B-cell ontogenesis, as well as cell fate decision towards the first-line/innate marginal zone (MZ) B-cell pool. Excess BLyS/BAFF is associated with hyperglobulinemia and increased frequencies of activated precursor-like MZ B-cells. Herein, we show that HIV highly-exposed seronegative (HESN) commercial sex workers (CSWs) had lower soluble BLyS/BAFF levels and relative frequencies of BLyS/BAFF expressing cells in their genital mucosa when compared to those from HIV-infected CSWs and HIV-uninfected non-CSWs. Furthermore, we identified genital innate and/or marginal zone (MZ)-like CD1c+ B-cells that naturally bind to fully glycosylated gp120, which frequencies were lower in HESNs when compared to HIV-infected CSWs and HIV-uninfected non-CSWs. Although genital levels of total IgA were similar between groups, HESNs had lower levels of total IgG1 and IgG3. Interestingly, HIV-gp41 reactive IgG1 were found in some HESNs. Low genital levels of BLyS/BAFF observed in HESNs may allow for controlled first-line responses, contributing to natural immunity to HIV.


Assuntos
Antígenos CD1/imunologia , Fator Ativador de Células B/imunologia , Linfócitos B/imunologia , Genitália Feminina/imunologia , Glicoproteínas/imunologia , Soronegatividade para HIV/imunologia , HIV-1/imunologia , Imunidade Inata , Profissionais do Sexo , Adulto , Linfócitos B/patologia , Feminino , Anticorpos Anti-HIV/imunologia , Humanos , Imunoglobulina G/imunologia , Pessoa de Meia-Idade
3.
Immunol Invest ; 48(7): 704-718, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31044626

RESUMO

Immunoglobulin-like transcript (ILT) 4 is an inhibitory immune receptor of the immunoglobulin superfamily, which could deliver inhibitory signals and induce immunosuppression. The significance of the expression of ILT4 in mDCs subsets in patients with hepatocellular carcinoma (HCC) remains unclear. In this study, the frequency of mDCs subsets in the peripheral blood of 121 patients with HCC and 103 normal controls, and in the tumor and tumor free liver tissues (TFL) of 43 HCC patients was analyzed by flow cytometry. Then, the expressions of ILT4 in mDCs subsets in the microenvironment of liver cancer were also analyzed. Results showed that the percentage of CD1c+ subset was dramatically decreased in peripheral blood mononuclear cells (PBMCs) of HCC patients compared with normal controls, and also significantly decreased in tumor tissue compared with the TFL. The decreased of CD1c+ subset in blood could be a diagnostic factor for HCC with the area under the receiver operating characteristic curve 0.975 (P < 0.01). The percentage of ILT4+CD1c+ subset was dramatically increased in tumor than that of TFL and blood. There were significant correlations between the percentage of ILT4+ in CD1c+ subset in tumor and that of in blood. The percentage of ILT4+CD1c+ subset in tumor tissue was strongly associated with the Edmondson-Steiner stage in HCC (P = 0.03). Furthermore, the capacity of ILT4+CD1c+ subset producing IFN-γ was lower than ILT4- CD1c subset in PBMC of HCC patients following Poly I:C stimulation. Taken together, the increased ILT4+CD1c+ subset in tumor tissue might play an important role in immune suppression for patients with HCC.


Assuntos
Carcinoma Hepatocelular/imunologia , Células Dendríticas/imunologia , Neoplasias Hepáticas/imunologia , Glicoproteínas de Membrana/imunologia , Células Mieloides/imunologia , Receptores Imunológicos/imunologia , Antígenos CD1/imunologia , Biomarcadores Tumorais/imunologia , Carcinoma Hepatocelular/sangue , Carcinoma Hepatocelular/patologia , Células Dendríticas/patologia , Feminino , Glicoproteínas/imunologia , Humanos , Interferon gama/metabolismo , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Células Mieloides/patologia , Poli I-C/farmacologia , Curva ROC , Microambiente Tumoral
4.
Blood ; 133(21): 2291-2304, 2019 05 23.
Artigo em Inglês | MEDLINE | ID: mdl-30796021

RESUMO

Relapsed/refractory T-cell acute lymphoblastic leukemia (T-ALL) has a dismal outcome, and no effective targeted immunotherapies for T-ALL exist. The extension of chimeric antigen receptor (CAR) T cells (CARTs) to T-ALL remains challenging because the shared expression of target antigens between CARTs and T-ALL blasts leads to CART fratricide. CD1a is exclusively expressed in cortical T-ALL (coT-ALL), a major subset of T-ALL, and retained at relapse. This article reports that the expression of CD1a is mainly restricted to developing cortical thymocytes, and neither CD34+ progenitors nor T cells express CD1a during ontogeny, confining the risk of on-target/off-tumor toxicity. We thus developed and preclinically validated a CD1a-specific CAR with robust and specific cytotoxicity in vitro and antileukemic activity in vivo in xenograft models of coT-ALL, using both cell lines and coT-ALL patient-derived primary blasts. CD1a-CARTs are fratricide resistant, persist long term in vivo (retaining antileukemic activity in re-challenge experiments), and respond to viral antigens. Our data support the therapeutic and safe use of fratricide-resistant CD1a-CARTs for relapsed/refractory coT-ALL.


Assuntos
Antígenos CD1/imunologia , Resistencia a Medicamentos Antineoplásicos/imunologia , Imunoterapia Adotiva , Leucemia-Linfoma Linfoblástico de Células T Precursoras , Receptores de Antígenos Quiméricos/imunologia , Animais , Humanos , Células Jurkat , Camundongos , Leucemia-Linfoma Linfoblástico de Células T Precursoras/imunologia , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patologia , Leucemia-Linfoma Linfoblástico de Células T Precursoras/terapia , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Tuberculosis (Edinb) ; 114: 9-16, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30711162

RESUMO

Tuberculosis (TB) is the main cause of mortality among all infectious diseases. The presentation of lipids by CD1b molecules and the interactions of the CD1b-lipid complexes with the immune receptors are important for the understanding of the immune response to Mycobacterium tuberculosis (Mtb), and to develop TB control methods. A specific domain antibody (dAbk11) recognizing the complex of CD1b with Mtb sulphoglycolipid (Ac2SGL) had been previously developed. In order to study the interactions of dAbk11 with Ac2SGL:CD1b, the conformation of Ac2SGL within CD1b was first modelled. The orientation of dAbκ11 with Ac2SGL:CD1b was then predicted by a docking experiment and the complex was sampled using molecular dynamics simulation. Data showed that dAbκ11 Tyr32 OH plays a decisive role in interacting with Ac2SGL alkyl tail HO17. The binding free energy calculation showed that Ac2SGL establish strong hydrophobic interactions with dAbκ11. The model also predicted a higher affinity for the natural sulfoglycolipid (Ac2SGL) than the synthetic analogue (SGL12), which was supported by the ELISA data. These results shed light on the likely mechanism of interactions between Ac2SGL:CD1b and dAbκ11, thus making possible to envision the strategies for dAbκ11 optimization for possible future applications.


Assuntos
Antígenos CD1/imunologia , Tuberculose/imunologia , Anticorpos Antibacterianos/imunologia , Apresentação do Antígeno/imunologia , Glicolipídeos/metabolismo , Humanos , Modelos Moleculares , Simulação de Acoplamento Molecular/métodos , Mycobacterium tuberculosis/imunologia
6.
Cancer Sci ; 110(3): 888-902, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30629318

RESUMO

Dendritic cells (DC) play a key role in the initiation of both antitumor immunity and immunological tolerance. It has been demonstrated that exposure to soluble factors produced by tumor cells modulates DC functions and induces tolerogenic DC differentiation. In this study, we investigated the effects of neuroblastoma cell line-derived soluble factors on DC differentiation. Monocytes isolated from healthy volunteers were incubated with interleukin (IL)-4 and granulocyte-macrophage colony-stimulating factor in the presence of culture supernatants from neuroblastoma cell lines. The culture supernatants from neuroblastoma cell lines, such as NLF and GOTO, partially blocked both downregulation of CD14 and upregulation of CD1a, and dramatically decreased IL-12 and tumor necrosis factor (TNF)-α production from mature DC, while no effect of SH-SY5Y cell supernatant was noted. In addition, IL-6 and IL-10 production from monocytes was increased by the supernatants of NLF and GOTO cells at 24 hours after incubation. Furthermore, we evaluated DC functions through stimulation of invariant natural killer T (iNKT) cells. α-Galactosylceramide-pulsed DC co-cultured with supernatants of NLF cells were unable to sufficiently stimulate iNKT cells. The decreased ability of iNKT cells to produce interferon (IFN)-γ after stimulation with neuroblastoma cell line supernatant-cultured DC was reversed by addition of IL-12. CD40 expression and IL-12 production in NLF-sup-treated DC were increased by addition of exogenous IFN-γ. These results indicate that tolerogenic DC are induced in the neuroblastoma tumor microenvironment and attenuate the antitumor effects of iNKT cells. Interactions between iNKT cells and αGalCer-pulsed DC have the potential to restore the immunosuppression of tolerogenic DC through IFN-γ production.


Assuntos
Diferenciação Celular/imunologia , Células Dendríticas/imunologia , Ativação Linfocitária/imunologia , Neuroblastoma/imunologia , Antígenos CD1/imunologia , Linhagem Celular , Linhagem Celular Tumoral , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Humanos , Interferon gama/imunologia , Interleucina-10/imunologia , Interleucina-12/imunologia , Interleucina-4/imunologia , Receptores de Lipopolissacarídeos/imunologia , Monócitos/imunologia , Monócitos/metabolismo
7.
Tuberculosis (Edinb) ; 113: 189-199, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30514502

RESUMO

The role of primary subsets of DCs in Mycobacterium tuberculosis infection in humans is incompletely understood. In this study, we identified a CD1c DC subset with phenotype of CD1c+CD11c+CD19-CD11b+ that was significantly increased in tuberculous pleural effusions and in peripheral blood from patients with TB compared with that from healthy controls (p < 0.0001). Sputum smear/culture-positive patients with tuberculosis had significantly higher frequency of CD1c+CD11b+ DC subset than sputum smear/culture-negative patients (p < 0.0001). After effective anti-TB chemotherapy, the frequency of CD1c+CD11b+ DC subset in peripheral blood and tuberculous pleural effusions was decreased. CD1c+CD11b+ DC subset from tuberculous pleural effusions expressed higher levels of TLR2, TLR4, CD172a, CD206 and FcεRⅠ, but lower levels of CD80, CD83 and CD86 compared with CD1c+CD11b- DC subset. Expression of IL-1ß, IL-6, IL-8, IL-23, TNF-α, IFN-γ and TGF-ß mRNA in CD1c+CD11b+ DCs was higher than in CD1c+CD11b- DC subset. Co-culture of autologous naive CD4+ T cells with sorted CD1c+CD11b+ DCs expressed significantly increased levels of IL-17A and RORγt transcripts as compared with those co-cultured with CD11b- subset. In conclusion, a CD1c+CD11b+ DC subset with elevated frequency in patients with tuberculosis was identified and it promoted Th17 cell differentiation.


Assuntos
Antígenos CD1/imunologia , Células Dendríticas/imunologia , Glicoproteínas/imunologia , Imunidade Inata , Pulmão/imunologia , Mycobacterium tuberculosis/imunologia , Células Th17/imunologia , Tuberculose Pulmonar/imunologia , Antituberculosos/uso terapêutico , Estudos de Casos e Controles , Diferenciação Celular , Células Cultivadas , Técnicas de Cocultura , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/microbiologia , Interações Hospedeiro-Patógeno , Humanos , Imunidade Inata/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Pulmão/microbiologia , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/patogenicidade , Fenótipo , Derrame Pleural/imunologia , Derrame Pleural/microbiologia , Células Th17/efeitos dos fármacos , Células Th17/microbiologia , Resultado do Tratamento , Tuberculose Pulmonar/sangue , Tuberculose Pulmonar/tratamento farmacológico , Tuberculose Pulmonar/microbiologia
8.
Mol Immunol ; 104: 27-36, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30399491

RESUMO

The CD1 family of glycoproteins are MHC class I-like molecules that present a wide array of self and foreign lipid antigens to T-cell receptors (TCRs) on T-cells. Humans express three classes of CD1 molecules, denoted as Group 1 (CD1a, CD1b, and CD1c), Group 2 (CD1d), and Group 3 (CD1e). Of the CD1 family of molecules, CD1b exhibits the largest and most complex antigen binding groove; allowing it the capabilities to present a broad spectrum of lipid antigens. While its role in foreign-lipid presentation in the context of mycobacterial infection are well characterized, understanding the roles of CD1b in autoreactivity are recently being elucidated. While the mechanisms governing proliferation of CD1b-restricted autoreactive T cells, regulation of CD1 gene expression, and the processes controlling CD1+ antigen presenting cell maturation are widely undercharacterized, the exploration of self-lipid antigens in the context of disease have recently come into focus. Furthermore, the recently expanded pool of CD1b crystal structures allow the opportunity to further analyze the molecular mechanisms of T-cell recognition and self-lipid presentation; where the intricacies of the two-compartment system, that accommodate both the presented self-lipid antigen and scaffold lipids, are scrutinized. This review delves into the immunological and molecular mechanisms governing presentation and T-cell recognition of the broad self-lipid repertoire of CD1b; with evidence mounting pointing towards a role in diseases such as microbial infection, autoimmune diseases, and cancer.


Assuntos
Apresentação do Antígeno , Antígenos CD1 , Autoantígenos , Lipídeos , Linfócitos T/imunologia , Animais , Antígenos CD1/química , Antígenos CD1/imunologia , Autoantígenos/química , Autoantígenos/imunologia , Cristalografia por Raios X , Humanos , Lipídeos/química , Lipídeos/imunologia , Relação Estrutura-Atividade
9.
Acta Chir Orthop Traumatol Cech ; 85(5): 351-358, 2018.
Artigo em Tcheco | MEDLINE | ID: mdl-30383532

RESUMO

PURPOSE OF THE STUDY This study deals with the possibilities and application of immunohistochemical methods to detect mast and dendritic cells in periprosthetic tissues in patients with aseptically loosened total joint replacements of the knee and hip. The purpose of the study was to quantify and characterize the distribution of mast and dendritic cells in the examined samples and to study the statistically significant relations between the aforementioned cell populations and selected parameters characterizing the patients, implants or tissue response. Based on the proved findings, a possible relation between mast and dendritic cells and histomorphological patterns of aseptic loosening and the benefit of the applied immunohistochemical methods was evaluated. MATERIAL AND METHODS Periprosthetic tissues from a total of 31 patients (17 patients after a revision surgery of hip prosthesis, 14 patients after a revision surgery of knee prosthesis) were examined. The collected samples were processed according to the standard protocol for the purposes of histological and immunochemical examination. Antibodies against tryptase and CD117 were used for immunohistochemical detection of mast cells. Dendritic cells were detected by means of S100 and CD1a antibodies. Quantification of both the cell populations was carried out by optical microscopy in 20 high power fields at 400-times magnification. From among the applied methods we picked the more sensitive one for statistical evaluation. It was tryptase in the case of mast cells and S100 in the case of dendritic cells. RESULTS Mast and dendritic cells were mostly distributed dispersively in periprosthetic tissues; however, they also occurred in groups perivasally or near necrotic parts. The examined samples showed the presence of 60 mast cells and 50 dendritic cells on average. The increased density of mast and dendritic cells was associated with polypously formed pseudosynovium and cement fixation of prostheses; this relation was statistically significant. It was impossible to prove the correlation between the quantity of the observed cell populations and the nature and the number of the observed particles because wear particles were present dispersely in all the samples. Another statistically significant relation to the type of material or implant fixation or other examined histomorphological patterns was not proved. A strong density of mast cells with a minimum presence of dendritic cells was observed in the control patient group. DISCUSSION The differences in density of S100 positive dendritic cells between the control and examined group of patients can be caused by the activation of dendritic cells by exogenous or endogenous pathways of immune processes going on after the implantation of endoprosthesis. The statistically significant interrelation of mast cells, polypously formed pseudosynovium and cement wear particles can be explained at least in part as a tissue reaction induced by cement particles. CONCLUSIONS We proved the presence of two immunologically significant cell populations in periprosthetic tissues. The said findings indicate a conclusion of significant functional participation of mast and dendritic cells in pathogenesis of aseptic loosening and periprosthetic osteolysis. Nevertheless, this will have to be proved in another way and with the use of another method. Key words:dendritic cells, mast cells, aseptic loosening, total joint replacement, immune reaction, adverse reaction.


Assuntos
Células Dendríticas/imunologia , Prótese de Quadril/microbiologia , Prótese do Joelho/microbiologia , Mastócitos/imunologia , Falha de Prótese/efeitos adversos , Antígenos CD1/imunologia , Células Dendríticas/ultraestrutura , Articulação do Quadril/microbiologia , Articulação do Quadril/patologia , Articulação do Quadril/cirurgia , Prótese de Quadril/efeitos adversos , Humanos , Articulação do Joelho/microbiologia , Articulação do Joelho/patologia , Articulação do Joelho/cirurgia , Prótese do Joelho/efeitos adversos , Mastócitos/ultraestrutura , Microscopia/instrumentação , Proteínas Proto-Oncogênicas c-kit/imunologia , Reoperação/métodos , Proteínas S100/imunologia , Triptases/imunologia
10.
Mol Immunol ; 103: 200-208, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30308433

RESUMO

Adoptive cell therapy (ACT) using tumor-specific "conventional" MHC-restricted T cells obtained from tumor-infiltrating lymphocytes, or derived ex vivo by either antigen-specific expansion or genetic engineering of polyclonal T cell populations, shows great promise for cancer treatment. However, the wide applicability of this therapy finds limits in the high polymorphism of MHC molecules that restricts the use in the autologous context. CD1 antigen presenting molecules are nonpolymorphic and specialized for lipid antigen presentation to T cells. They are often expressed on malignant cells and, therefore, may represent an attractive target for ACT. We provide a brief overview of the CD1-resticted T cell response in tumor immunity and we discuss the pros and cons of ACT approaches based on unconventional CD1-restricted T cells.


Assuntos
Antígenos CD1/imunologia , Imunoterapia Adotiva/métodos , Neoplasias/terapia , Linfócitos T/imunologia , Animais , Apresentação do Antígeno/imunologia , Células Apresentadoras de Antígenos/imunologia , Humanos , Lipídeos/imunologia , Complexo Principal de Histocompatibilidade/imunologia , Neoplasias/imunologia , Linfócitos T/transplante
11.
Front Immunol ; 9: 2205, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30319649

RESUMO

Regulation of T cell-mediated immunity in the lungs is critical for prevention of immune-related lung disorders and for host protection from pathogens. While the prevalent view of pulmonary T cell responses is based on peptide recognition by antigen receptors, called T cell receptors (TCR), on the T cell surface in the context of classical major histocompatibility complex (MHC) molecules, novel pathways involving the presentation of lipid antigens by cluster of differentiation 1 (CD1) molecules to lipid-reactive T cells are emerging as key players in pulmonary immune system. Whereas, genetic conservation of group II CD1 (CD1d) in mouse and human genomes facilitated numerous in vivo studies of CD1d-restricted invariant natural killer T (iNKT) cells in lung diseases, the recent development of human CD1-transgenic mice has made it possible to examine the physiological roles of group I CD1 (CD1a-c) molecules in lung immunity. Here, we discuss current understanding of the biology of CD1-reactive T cells with a specific focus on their roles in several pulmonary disorders.


Assuntos
Antígenos CD1/imunologia , Antígenos/imunologia , Lipídeos/imunologia , Pneumopatias/imunologia , Células T Matadoras Naturais/imunologia , Animais , Antígenos CD1/genética , Modelos Animais de Doenças , Humanos , Pulmão/citologia , Pulmão/imunologia , Pneumopatias/genética , Ativação Linfocitária , Camundongos Transgênicos , Células T Matadoras Naturais/metabolismo , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo
12.
J Immunol ; 201(10): 3006-3016, 2018 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-30322965

RESUMO

Human mucosal tissues and skin contain two distinct types of dendritic cell (DC) subsets, epidermal Langerhans cells (LCs) and dermal DCs, which can be distinguished by the expression of C-type lectin receptors, Langerin and DC-SIGN, respectively. Although peripheral blood monocytes differentiate into these distinct subsets, monocyte-derived LCs (moLCs) induced by coculture with GM-CSF, IL-4, and TGF-ß1 coexpress both Langerin and DC-SIGN, suggesting that the environmental cues remain unclear. In this study, we show that LC differentiation is TGF-ß1 dependent and that cofactors such as IL-4 and TNF-α promote TGF-ß1-dependent LC differentiation into Langerin+DC-SIGN- moLCs but continuous exposure to IL-4 blocks differentiation. Steroids such as dexamethasone greatly enhanced TNF-α-induced moLC differentiation and blocked DC-SIGN expression. Consistent with primary LCs, dexamethasone-treated moLCs express CD1a, whereas monocyte-derived DCs (moDCs) express CD1b, CD1c, and CD1d. moDCs but not moLCs produced inflammatory cytokines after stimulation with CD1b and CD1d ligands mycolic acid and α-galactosylceramide, respectively. Strikingly, CD1a triggering with squalene on moLCs but not moDCs induced strong IL-22-producing CD4+ helper T cell responses. As IL-22 is an important cytokine in the maintenance of skin homeostasis, these data suggest that CD1a on LCs is involved in maintaining the immune barrier in the skin.


Assuntos
Diferenciação Celular/imunologia , Células de Langerhans/imunologia , Monócitos/imunologia , Pele/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Antígenos CD1/imunologia , Células Cultivadas , Células Dendríticas/imunologia , Humanos , Interleucinas/imunologia , Células de Langerhans/citologia , Ativação Linfocitária/imunologia , Monócitos/citologia , Pele/citologia
13.
Cancer Immunol Immunother ; 67(9): 1425-1436, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30019146

RESUMO

There has recently been a paradigm shift in the field of dendritic cell (DC)-based immunotherapy, where several clinical studies have confirmed the feasibility and advantageousness of using directly isolated human blood-derived DCs over in vitro differentiated subsets. There are two major DC subsets found in blood; plasmacytoid DCs (pDCs) and myeloid DCs (mDCs), and both have been tested clinically. CD1c+ mDCs are highly efficient antigen-presenting cells that have the ability to secrete IL-12p70, while pDCs are professional IFN-α-secreting cells that are shown to induce innate immune responses in melanoma patients. Hence, combining mDCs and pDCs poses as an attractive, multi-functional vaccine approach. However, type I IFNs have been reported to inhibit IL-12p70 production and mDC-induced T-cell activation. In this study, we investigate the effect of IFN-α on mDC maturation and function. We demonstrate that both recombinant IFN-α and activated pDCs strongly enhance mDC maturation and increase IL-12p70 production. Co-cultured mDCs and pDCs additionally have beneficial effect on NK and NKT-cell activation and also enhances IFN-γ production by allogeneic T cells. In contrast, the presence of type I IFNs reduces the proliferative T-cell response. The mere presence of a small fraction of activated pDCs is sufficient for these effects and the required ratio between the subsets is non-stringent. Taken together, these results support the usage of mDCs and pDCs combined into one immunotherapeutic vaccine with broad immunostimulatory features.


Assuntos
Células Dendríticas/imunologia , Interferon Tipo I/farmacologia , Interleucina-12/biossíntese , Células Mieloides/imunologia , Antígenos CD1/imunologia , Antígenos CD1/farmacologia , Técnicas de Cocultura , Células Dendríticas/citologia , Células Dendríticas/efeitos dos fármacos , Glicoproteínas/imunologia , Glicoproteínas/farmacologia , Humanos , Imunidade Inata , Interferon Tipo I/imunologia , Interferon alfa-2 , Interferon-alfa/imunologia , Interferon-alfa/farmacologia , Interferon gama/biossíntese , Interferon gama/imunologia , Interleucina-12/imunologia , Interleucina-12/farmacologia , Ativação Linfocitária , Células Mieloides/citologia , Células Mieloides/efeitos dos fármacos , Quinolinas/farmacologia , Proteínas Recombinantes/imunologia , Proteínas Recombinantes/farmacologia , Linfócitos T/citologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia
14.
J Immunol ; 201(3): 888-896, 2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-29914888

RESUMO

Human T cells that recognize lipid Ags presented by highly conserved CD1 proteins often express semi-invariant TCRs, but the true diversity of lipid Ag-specific TCRs remains unknown. We use CD1b tetramers and high-throughput immunosequencing to analyze thousands of TCRs from ex vivo-sorted or in vitro-expanded T cells specific for the mycobacterial lipid Ag, glucose monomycolate. Our results reveal a surprisingly diverse repertoire resulting from editing of germline-encoded gene rearrangements analogous to MHC-restricted TCRs. We used a distance-based metric (TCRDist) to show how this diverse TCR repertoire builds upon previously reported conserved motifs by including subject-specific TCRs. In a South African cohort, we show that TCRDist can identify clonal expansion of diverse glucose monomycolate-specific TCRs and accurately distinguish patients with active tuberculosis from control subjects. These data suggest that similar mechanisms govern the selection and expansion of peptide and lipid Ag-specific T cells despite the nonpolymorphic nature of CD1.


Assuntos
Antígenos CD1/imunologia , Lipídeos/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Tuberculose/imunologia , Adolescente , Linhagem Celular Tumoral , Células Cultivadas , Criança , Feminino , Humanos , Células K562 , Masculino , Mycobacterium/imunologia , Linfócitos T
15.
Front Immunol ; 9: 744, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29755453

RESUMO

Dendritic cells (DCs) are major players for the induction of immune responses. Apart from plasmacytoid DCs (pDCs), human DCs can be categorized into two types of conventional DCs: CD141+ DCs (cDC1) and CD1c+ DCs (cDC2). Defining uniquely expressed surface markers on human immune cells is not only important for the identification of DC subpopulations but also a prerequisite for harnessing the DC subset-specific potential in immunomodulatory approaches, such as antibody-mediated antigen targeting. Although others identified CLEC9A as a specific endocytic receptor for CD141+ DCs, such a receptor for CD1c+ DCs has not been discovered, yet. By performing transcriptomic and flow cytometric analyses on human DC subpopulations from different lymphohematopoietic tissues, we identified CLEC10A (CD301, macrophage galactose-type C-type lectin) as a specific marker for human CD1c+ DCs. We further demonstrate that CLEC10A rapidly internalizes into human CD1c+ DCs upon binding of a monoclonal antibody directed against CLEC10A. The binding of a CLEC10A-specific bivalent ligand (the MUC-1 peptide glycosylated with N-acetylgalactosamine) is limited to CD1c+ DCs and enhances the cytokine secretion (namely TNFα, IL-8, and IL-10) induced by TLR 7/8 stimulation. Thus, CLEC10A represents not only a candidate to better define CD1c+ DCs-due to its high endocytic potential-CLEC10A also exhibits an interesting candidate receptor for future antigen-targeting approaches.


Assuntos
Antígenos CD1/imunologia , Células Dendríticas/imunologia , Glicoproteínas/imunologia , Lectinas Tipo C/imunologia , Adulto , Citocinas/imunologia , Humanos , Mucina-1/imunologia , Receptor 7 Toll-Like/imunologia , Receptor 8 Toll-Like/imunologia
16.
Curr Opin Immunol ; 52: 93-99, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29738961

RESUMO

Peptide and lipid antigens are presented to T cells when bound to MHC or CD1 proteins, respectively. The general paradigm of T cell antigen recognition is that T cell receptors (TCRs) co-recognize an epitope comprised of the antigen and antigen presenting molecule. Here we review the latest studies in which T cells operate outside the co-recognition paradigm: TCRs can broadly contact CD1 itself, but not the carried lipid. The essential structural feature in these new mechanisms is a large 'antigen free' zone on the outer surface of certain antigen presenting molecules. Whereas peptides dominate the exposed surface of MHC-peptide complexes, all human CD1 proteins have a closed, antigen-free surface, which is known as the A' roof. These new structural models help to interpret recent biological studies of CD1 autoreactive T cells in vivo, which have now been broadly observed in studies on TCR-transgenic mice, healthy humans and patients with autoimmune disease.


Assuntos
Antígenos CD1/imunologia , Antígenos CD1/metabolismo , Autoimunidade , Lipídeos/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Animais , Apresentação do Antígeno , Antígenos/química , Antígenos/imunologia , Antígenos CD1/química , Humanos , Ligantes , Lipídeos/química , Ativação Linfocitária , Receptores de Antígenos de Linfócitos T/química
17.
J Immunol Methods ; 458: 44-52, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29684428

RESUMO

CD1 tetramers loaded with lipid antigens facilitate the identification of rare lipid-antigen specific T cells present in human blood and tissue. Because CD1 proteins are structurally non-polymorphic, these tetramers can be applied to genetically diverse human populations, unlike MHC-I and MHC-II tetramers. However, there are no standardized assays to quantify and characterize lipid antigen-specific T cells present within clinical samples. We incorporated CD1b tetramers loaded with the mycobacterial lipid glucose monomycolate (GMM) into a multi-parameter flow cytometry assay. Using a GMM-specific T-cell line, we demonstrate that the assay is linear, reproducible, repeatable, precise, accurate, and has a limit of detection of approximately 0.007%. Having formally validated this assay, we performed a cross-sectional study of healthy U.S. controls and South African adolescents with and without latent tuberculosis infection (LTBI). We show that GMM-specific T cells are specifically detected in South African subjects with LTBI and not in U.S. healthy controls. This assay can be expanded to include additional tetramers or phenotypic markers to characterize GMM-specific T cells in studies of mycobacterial infection, disease, or vaccination.


Assuntos
Antígenos CD1/imunologia , Citometria de Fluxo/métodos , Tuberculose Latente/diagnóstico , Mycobacterium tuberculosis/isolamento & purificação , Linfócitos T/imunologia , Adolescente , Adulto , Antígenos de Bactérias/imunologia , Antígenos CD1/metabolismo , Técnicas de Cultura de Células , Linhagem Celular , Estudos Transversais , Epitopos de Linfócito T/imunologia , Citometria de Fluxo/instrumentação , Glicolipídeos/química , Glicolipídeos/imunologia , Voluntários Saudáveis , Humanos , Imunogenicidade da Vacina , Tuberculose Latente/imunologia , Tuberculose Latente/microbiologia , Tuberculose Latente/prevenção & controle , Mycobacterium tuberculosis/imunologia , Multimerização Proteica/imunologia , África do Sul , Linfócitos T/metabolismo , Vacinas contra a Tuberculose/administração & dosagem , Vacinas contra a Tuberculose/imunologia , Estados Unidos
18.
Nat Immunol ; 19(4): 397-406, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29531339

RESUMO

The hallmark function of αß T cell antigen receptors (TCRs) involves the highly specific co-recognition of a major histocompatibility complex molecule and its carried peptide. However, the molecular basis of the interactions of TCRs with the lipid antigen-presenting molecule CD1c is unknown. We identified frequent staining of human T cells with CD1c tetramers across numerous subjects. Whereas TCRs typically show high specificity for antigen, both tetramer binding and autoreactivity occurred with CD1c in complex with numerous, chemically diverse self lipids. Such extreme polyspecificity was attributable to binding of the TCR over the closed surface of CD1c, with the TCR covering the portal where lipids normally protrude. The TCR essentially failed to contact lipids because they were fully seated within CD1c. These data demonstrate the sequestration of lipids within CD1c as a mechanism of autoreactivity and point to small lipid size as a determinant of autoreactive T cell responses.


Assuntos
Antígenos CD1/imunologia , Autoantígenos/imunologia , Autoimunidade/imunologia , Glicoproteínas/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Linfócitos T/imunologia , Apresentação do Antígeno/imunologia , Humanos , Lipídeos/imunologia , Ativação Linfocitária/imunologia
19.
Cell Chem Biol ; 25(4): 392-402.e14, 2018 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-29398561

RESUMO

Mycobacterial cell wall lipids bind the conserved CD1 family of antigen-presenting molecules and activate T cells via their T cell receptors (TCRs). Sulfoglycolipids (SGLs) are uniquely synthesized by Mycobacterium tuberculosis, but tools to study SGL-specific T cells in humans are lacking. We designed a novel hybrid synthesis of a naturally occurring SGL, generated CD1b tetramers loaded with natural or synthetic SGL analogs, and studied the molecular requirements for TCR binding and T cell activation. Two T cell lines derived using natural SGLs are activated by synthetic analogs independently of lipid chain length and hydroxylation, but differentially by saturation status. By contrast, two T cell lines derived using an unsaturated SGL synthetic analog were not activated by the natural antigen. Our data provide a bioequivalence hierarchy of synthetic SGL analogs and SGL-loaded CD1b tetramers. These reagents can now be applied to large-scale translational studies investigating the diagnostic potential of SGL-specific T cell responses or SGL-based vaccines.


Assuntos
Antígenos de Bactérias/imunologia , Antígenos CD1/imunologia , Glicolipídeos/imunologia , Ativação Linfocitária , Mycobacterium tuberculosis/imunologia , Linfócitos T/imunologia , Tuberculose/imunologia , Acilação , Antígenos CD1/química , Linhagem Celular , Glicolipídeos/química , Humanos , Modelos Moleculares , Mycobacterium tuberculosis/química , Multimerização Proteica
20.
Immunology ; 154(2): 196-203, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29460282

RESUMO

The family of non-classical major histocompatibility complex (MHC) class-I like CD1 molecules has an emerging role in human disease. Group 1 CD1 includes CD1a, CD1b and CD1c, which function to display lipids on the cell surface of antigen-presenting cells for direct recognition by T-cells. The recent advent of CD1 tetramers and the identification of novel lipid ligands has contributed towards the increasing number of CD1-restricted T-cell clones captured. These advances have helped to identify novel donor unrestricted and semi-invariant T-cell populations in humans and new mechanisms of T-cell recognition. However, although there is an opportunity to design broadly acting lipids and harness the therapeutic potential of conserved T-cells, knowledge of their role in health and disease is lacking. We briefly summarize the current evidence implicating group 1 CD1 molecules in infection, cancer and autoimmunity and show that although CD1 are not as diverse as MHC, recent discoveries highlight their versatility as they exhibit intricate mechanisms of antigen presentation.


Assuntos
Apresentação do Antígeno/imunologia , Antígenos CD1/imunologia , Lipídeos/imunologia , Transdução de Sinais , Animais , Antígenos CD1/química , Antígenos CD1/metabolismo , Autoimunidade , Suscetibilidade a Doenças , Humanos , Interações Hidrofóbicas e Hidrofílicas , Ligantes , Relação Estrutura-Atividade , Linfócitos T/imunologia , Linfócitos T/metabolismo
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