RESUMO
Expressed on epidermal Langerhans cells, CD1a presents a range of self-lipid antigens found within the skin; however, the extent to which CD1a presents microbial ligands from bacteria colonizing the skin is unclear. Here we identified CD1a-dependent T cell responses to phosphatidylglycerol (PG), a ubiquitous bacterial membrane phospholipid, as well as to lysylPG, a modified PG, present in several Gram-positive bacteria and highly abundant in Staphylococcus aureus. The crystal structure of the CD1a-PG complex showed that the acyl chains were buried within the A'- and F'-pockets of CD1a, while the phosphoglycerol headgroup remained solvent exposed in the F'-portal and was available for T cell receptor contact. Using lysylPG and PG-loaded CD1a tetramers, we identified T cells in peripheral blood and in skin that respond to these lipids in a dose-dependent manner. Tetramer+CD4+ T cell lines secreted type 2 helper T cell cytokines in response to phosphatidylglycerols as well as to co-cultures of CD1a+ dendritic cells and Staphylococcus bacteria. The expansion in patients with atopic dermatitis of CD4+ CD1a-(lysyl)PG tetramer+ T cells suggests a response to lipids made by bacteria associated with atopic dermatitis and provides a link supporting involvement of PG-based lipid-activated T cells in atopic dermatitis pathogenesis.
Assuntos
Dermatite Atópica , Humanos , Pele , Células de Langerhans , Antígenos CD1 , Autoantígenos/metabolismo , Staphylococcus/metabolismo , FosfatidilgliceróisRESUMO
Hundreds of human cullin-RING E3 ligases (CRLs) modify thousands of proteins with ubiquitin (UB) to achieve vast regulation. Current dogma posits that CRLs first catalyze UB transfer from an E2 to their client substrates and subsequent polyubiquitylation from various linkage-specific E2s. We report an alternative E3-E3 tagging cascade: many cellular NEDD8-modified CRLs associate with a mechanistically distinct thioester-forming RBR-type E3, ARIH1, and rely on ARIH1 to directly add the first UB and, in some cases, multiple additional individual monoubiquitin modifications onto CRL client substrates. Our data define ARIH1 as a component of the human CRL system, demonstrate that ARIH1 can efficiently and specifically mediate monoubiquitylation of several CRL substrates, and establish principles for how two distinctive E3s can reciprocally control each other for simultaneous and joint regulation of substrate ubiquitylation. These studies have broad implications for CRL-dependent proteostasis and mechanisms of E3-mediated UB ligation.
Assuntos
Proteínas de Transporte/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitina/metabolismo , Ubiquitinação , Ubiquitinas/metabolismo , Proteínas de Transporte/genética , Proteínas Culina/metabolismo , Técnicas de Silenciamento de Genes , Células HEK293 , Humanos , Mutação , Proteína NEDD8 , Poliubiquitina/metabolismo , Proteômica , Especificidade por Substrato , Enzimas de Conjugação de Ubiquitina/metabolismoRESUMO
A central paradigm in αß T cell-mediated immunity is the simultaneous co-recognition of antigens and antigen-presenting molecules by the αß T cell antigen receptor (TCR). CD1a presents a broad repertoire of lipid-based antigens. We found that a prototypical autoreactive TCR bound CD1a when it was presenting a series of permissive endogenous ligands, while other lipid ligands were nonpermissive to TCR binding. The structures of two TCR-CD1a-lipid complexes showed that the TCR docked over the A' roof of CD1a in a manner that precluded direct contact with permissive ligands. Nonpermissive ligands indirectly inhibited TCR binding by disrupting the TCR-CD1a contact zone. The exclusive recognition of CD1a by the TCR represents a previously unknown mechanism whereby αß T cells indirectly sense self antigens that are bound to an antigen-presenting molecule.
Assuntos
Apresentação de Antígeno/imunologia , Antígenos CD1/imunologia , Autoantígenos/imunologia , Lipídeos/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Linfócitos T/imunologia , Linhagem Celular , Linhagem Celular Tumoral , Células HEK293 , Humanos , Células Jurkat , Ligantes , Ligação ProteicaRESUMO
T cells autoreactive to the antigen-presenting molecule CD1a are common in human blood and skin, but the search for natural autoantigens has been confounded by background T cell responses to CD1 proteins and self lipids. After capturing CD1a-lipid complexes, we gently eluted ligands while preserving non-ligand-bound CD1a for testing lipids from tissues. CD1a released hundreds of ligands of two types. Inhibitory ligands were ubiquitous membrane lipids with polar head groups, whereas stimulatory compounds were apolar oils. We identified squalene and wax esters, which naturally accumulate in epidermis and sebum, as autoantigens presented by CD1a. The activation of T cells by skin oils suggested that headless mini-antigens nest within CD1a and displace non-antigenic resident lipids with large head groups. Oily autoantigens naturally coat the surface of the skin; thus, this points to a previously unknown mechanism of barrier immunity.
Assuntos
Antígenos CD1/imunologia , Autoantígenos/imunologia , Lipídeos/imunologia , Pele/imunologia , Linfócitos T/imunologia , Sequência de Aminoácidos , Apresentação de Antígeno , Antígenos CD1/genética , Autoantígenos/química , Autoantígenos/isolamento & purificação , Células HEK293 , Humanos , Interações Hidrofóbicas e Hidrofílicas , Lipídeos/química , Lipídeos/isolamento & purificação , Ativação Linfocitária , Dados de Sequência Molecular , Ligação Proteica , Proteínas Recombinantes/genética , Relação Estrutura-AtividadeRESUMO
Human T cell antigen receptors (TCRs) pair in millions of combinations to create complex and unique T cell repertoires for each person. Through the use of tetramers to analyze TCRs reactive to the antigen-presenting molecule CD1b, we detected T cells with highly stereotyped TCR α-chains present among genetically unrelated patients with tuberculosis. The germline-encoded, mycolyl lipid-reactive (GEM) TCRs had an α-chain bearing the variable (V) region TRAV1-2 rearranged to the joining (J) region TRAJ9 with few nontemplated (N)-region additions. Analysis of TCRs by high-throughput sequencing, binding and crystallography showed linkage of TCRα sequence motifs to high-affinity recognition of antigen. Thus, the CD1-reactive TCR repertoire is composed of at least two compartments: high-affinity GEM TCRs, and more-diverse TCRs with low affinity for CD1b-lipid complexes. We found high interdonor conservation of TCRs that probably resulted from selection by a nonpolymorphic antigen-presenting molecule and an immunodominant antigen.
Assuntos
Antígenos CD1/imunologia , Infecções por Mycobacterium/imunologia , Mycobacterium/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T/imunologia , Sequência de Aminoácidos , Sequência de Bases , Células Clonais , Cristalografia por Raios X , Citometria de Fluxo , Humanos , Modelos Moleculares , Dados de Sequência Molecular , Infecções por Mycobacterium/microbiologia , RNA/química , RNA/genética , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Análise de Sequência de DNA , Subpopulações de Linfócitos T/citologia , Linfócitos T/citologiaRESUMO
CD1 activates T cells, but the function and size of the possible human T cell repertoires that recognize each of the CD1 antigen-presenting molecules remain unknown. Using an experimental system that bypasses major histocompatibility complex (MHC) restriction and the requirement for defined antigens, we show that polyclonal T cells responded at higher rates to cells expressing CD1a than to those expressing CD1b, CD1c or CD1d. Unlike the repertoire of invariant natural killer T (NKT) cells, the CD1a-autoreactive repertoire contained diverse T cell antigen receptors (TCRs). Functionally, many CD1a-autoreactive T cells homed to skin, where they produced interleukin 22 (IL-22) in response to CD1a on Langerhans cells. The strong and frequent responses among genetically diverse donors define CD1a-autoreactive cells as a normal part of the human T cell repertoire and CD1a as a target of the T(H)22 subset of helper T cells.
Assuntos
Antígenos CD1/imunologia , Autoimunidade/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Pele/imunologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Separação Celular , Quimiotaxia de Leucócito/imunologia , ELISPOT , Citometria de Fluxo , Humanos , Interleucinas/imunologia , Interleucinas/metabolismo , Células de Langerhans/imunologia , Células de Langerhans/metabolismo , Ativação Linfocitária/imunologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Pele/citologia , Subpopulações de Linfócitos T/citologia , Subpopulações de Linfócitos T/metabolismo , Linfócitos T Auxiliares-Indutores/citologia , Linfócitos T Auxiliares-Indutores/metabolismo , Interleucina 22RESUMO
Infected or transformed cells must present peptides derived from endogenous proteins on MHC class I molecules to be recognized and targeted for elimination by Ag-specific cytotoxic T cells. In the first step of peptide generation, proteins are degraded by the proteasome. In this study, we investigated the role of the ubiquitin-specific protease 14 (Usp14), a proteasome-associated deubiquitinase, in direct Ag presentation using a ligand-stabilized model protein expressed as a self-antigen. Chemical inhibition of Usp14 diminished direct presentation of the model antigenic peptide, and the effect was especially pronounced when presentation was restricted to the defective ribosomal product (DRiP) form of the protein. Additionally, presentation specifically from DRiP Ags was diminished by expression of a catalytically inactive form of Usp14. Usp14 inhibition did not appreciably alter protein synthesis and only partially delayed protein degradation as measured by a slight increase in the half-life of the model protein when its degradation was induced. Taken together, these data indicate that functional Usp14 enhances direct Ag presentation, preferentially of DRiP-derived peptides, suggesting that the processing of DRiPs is in some ways different from other forms of Ag.
Assuntos
Apresentação de Antígeno/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Peptídeos/imunologia , Linfócitos T Citotóxicos/imunologia , Ubiquitina Tiolesterase/antagonistas & inibidores , Animais , Apresentação de Antígeno/efeitos dos fármacos , Linhagem Celular Tumoral , Camundongos , Biossíntese de Proteínas , Proteólise , Pirróis/farmacologia , Pirrolidinas/farmacologiaRESUMO
Over two decades ago, it was discovered that the human T-cell repertoire contains T cells that do not recognize peptide antigens in the context of MHC molecules but instead respond to lipid antigens presented by CD1 antigen-presenting molecules. The ability of T cells to 'see' lipid antigens bound to CD1 enables these lymphocytes to sense changes in the lipid composition of cells and tissues as a result of infections, inflammation, or malignancies. Although foreign lipid antigens have been shown to function as antigens for CD1-restricted T cells, many CD1-restricted T cells do not require foreign antigens for activation but instead can be activated by self-lipids presented by CD1. This review highlights recent developments in the field, including the identification of common mammalian lipids that function as autoantigens for αß and γδ T cells, a novel mode of T-cell activation whereby CD1a itself rather than lipids serves as the autoantigen, and various mechanisms by which the activation of CD1-autoreactive T cells is regulated. As CD1 can induce T-cell effector functions in the absence of foreign antigens, multiple mechanisms are in place to regulate this self-reactivity, and stimulatory CD1-lipid complexes appear to be tightly controlled in space and time.
Assuntos
Antígenos CD1/imunologia , Autoantígenos/imunologia , Lipídeos/imunologia , Ativação Linfocitária/imunologia , Linfócitos T/imunologia , Animais , Apresentação de Antígeno/imunologia , Antígenos CD1/metabolismo , Humanos , Lipídeos/química , Modelos Imunológicos , Receptores de Antígenos de Linfócitos T/imunologia , Linfócitos T/metabolismoRESUMO
Alopecia areata (AA) is an autoimmune disease of the hair follicle that results in hair loss of varying severity. Recently, we showed that IFN-γ-producing NKG2D(+)CD8(+) T cells actively infiltrate the hair follicle and are responsible for its destruction in C3H/HeJ AA mice. Our transcriptional profiling of human and mouse alopecic skin showed that the IFN pathway is the dominant signaling pathway involved in AA. We showed that IFN-inducible chemokines (CXCL9/10/11) are markedly upregulated in the skin of AA lesions, and further, that the IFN-inducible chemokine receptor, CXCR3, is upregulated on alopecic effector T cells. To demonstrate whether CXCL9/10/11 chemokines were required for development of AA, we treated mice with blocking Abs to CXCR3, which prevented the development of AA in the graft model, inhibiting the accumulation of NKG2D(+)CD8(+) T cells in the skin and cutaneous lymph nodes. These data demonstrate proof of concept that interfering with the Tc1 response in AA via blockade of IFN-inducible chemokines can prevent the onset of AA. CXCR3 blockade could be approached clinically in human AA with either biologic or small-molecule inhibition, the latter being particularly intriguing as a topical therapeutic.
Assuntos
Alopecia em Áreas/imunologia , Receptores CXCR3/antagonistas & inibidores , Linfócitos T/imunologia , Animais , Quimiotaxia de Leucócito/imunologia , Modelos Animais de Doenças , Citometria de Fluxo , Imunofluorescência , Humanos , Imuno-Histoquímica , Camundongos , Camundongos Endogâmicos C3H , Reação em Cadeia da Polimerase , Receptores CXCR3/biossíntese , Pele/imunologiaRESUMO
The proteasome is able to create spliced Ags, in which two distant parts of a protein are excised and ligated together to form a novel peptide, for presentation by MHC class I molecules. These noncontiguous epitopes are generated via a transpeptidation reaction catalyzed by the proteasomal active sites. Transpeptidation reactions in the proteasome follow explicit rules and occur particularly efficiently when the C-terminal ligation partner contains a lysine or arginine residue at the site of ligation. Lysine contains two amino groups that theoretically may both participate in ligation reactions, implying that potentially not only peptide but also isopeptide linkages could be formed. Using nuclear magnetic resonance spectroscopy, we demonstrate in the present study that the proteasome can use the ε-amino group of an N-terminal lysine residue in transpeptidation reactions to create a novel type of posttranslationally modified epitopes. We show that the overall efficiency of ε ligation is only 10-fold lower as compared with α ligation, suggesting that the proteasome can produce sufficient isopeptide Ag to evoke a T cell response. Additionally, we show that isopeptides are more stable toward further proteasomal processing than are normal peptides, and we demonstrate that isopeptides can bind to HLA-A2.1 and HLA-A3 with high affinity. These properties likely increase the fraction of ε-ligated peptides presented on the cell surface for CD8(+) T cell surveillance. Finally, we show that isopeptide Ags are immunogenic in vivo. We postulate that ε ligation is a genuine posttranslational modification, suggesting that the proteasome can create a novel type of Ag that is likely to play a role in immunity.
Assuntos
Peptídeos/química , Complexo de Endopeptidases do Proteassoma/química , Processamento de Proteína , Humanos , Espectroscopia de Ressonância Magnética , Peptídeos/imunologia , Complexo de Endopeptidases do Proteassoma/imunologia , Isoformas de Proteínas/química , Isoformas de Proteínas/imunologia , Processamento de Proteína Pós-Traducional , Linfócitos T/imunologiaRESUMO
Peptide splicing, in which two distant parts of a protein are excised and then ligated to form a novel peptide, can generate unique MHC class I-restricted responses. Because these peptides are not genetically encoded and the rules behind proteasomal splicing are unknown, it is difficult to predict these spliced Ags. In the current study, small libraries of short peptides were used to identify amino acid sequences that affect the efficiency of this transpeptidation process. We observed that splicing does not occur at random, neither in terms of the amino acid sequences nor through random splicing of peptides from different sources. In contrast, splicing followed distinct rules that we deduced and validated both in vitro and in cells. Peptide ligation was quantified using a model peptide and demonstrated to occur with up to 30% ligation efficiency in vitro, provided that optimal structural requirements for ligation were met by both ligating partners. In addition, many splicing products could be formed from a single protein. Our splicing rules will facilitate prediction and detection of new spliced Ags to expand the peptidome presented by MHC class I Ags.
Assuntos
Apresentação de Antígeno , Antígenos de Histocompatibilidade Classe I/imunologia , Peptídeos/imunologia , Complexo de Endopeptidases do Proteassoma/química , Processamento de Proteína , Sequência de Aminoácidos , Humanos , Dados de Sequência Molecular , Complexo de Endopeptidases do Proteassoma/imunologiaRESUMO
Deubiquitinating enzymes (DUBs) catalyze the cleavage of ubiquitin from target proteins. Ubiquitin is post-translationally attached to proteins and serves as an important regulatory signal for key cellular processes. In this study, novel activity-based probes to study DUBs were synthesized that comprise a ubiquitin moiety and a novel disulfide warhead at the C-terminus. These reagents can bind DUBs covalently by forming a disulfide bridge between the active-site cysteine residue and the ubiquitin-based probe. As disulfide bridges can be broken by the addition of a reducing agent, these novel ubiquitin reagents can be used to capture and subsequently release catalytically active DUBs, whereas existing capturing agents bind irreversibly. These novel reagents allow for the study of these enzymes in their active state under various conditions.
Assuntos
Enzimas Desubiquitinantes/metabolismo , Dissulfetos/química , Ubiquitina/metabolismo , Biotina/química , Domínio Catalítico , Cisteína/química , Enzimas Desubiquitinantes/química , Dissulfetos/metabolismo , Células HeLa , Humanos , Polietilenoglicóis/química , Proteínas/metabolismo , Ubiquitina/química , UbiquitinaçãoRESUMO
Viral infection triggers an early host response through activation of pattern recognition receptors, including Toll-like receptors (TLR). TLR signaling cascades induce production of type I interferons and proinflammatory cytokines involved in establishing an anti-viral state as well as in orchestrating ensuing adaptive immunity. To allow infection, replication, and persistence, (herpes)viruses employ ingenious strategies to evade host immunity. The human gamma-herpesvirus Epstein-Barr virus (EBV) is a large, enveloped DNA virus persistently carried by more than 90% of adults worldwide. It is the causative agent of infectious mononucleosis and is associated with several malignant tumors. EBV activates TLRs, including TLR2, TLR3, and TLR9. Interestingly, both the expression of and signaling by TLRs is attenuated during productive EBV infection. Ubiquitination plays an important role in regulating TLR signaling and is controlled by ubiquitin ligases and deubiquitinases (DUBs). The EBV genome encodes three proteins reported to exert in vitro deubiquitinase activity. Using active site-directed probes, we show that one of these putative DUBs, the conserved herpesvirus large tegument protein BPLF1, acts as a functional DUB in EBV-producing B cells. The BPLF1 enzyme is expressed during the late phase of lytic EBV infection and is incorporated into viral particles. The N-terminal part of the large BPLF1 protein contains the catalytic site for DUB activity and suppresses TLR-mediated activation of NF-κB at, or downstream of, the TRAF6 signaling intermediate. A catalytically inactive mutant of this EBV protein did not reduce NF-κB activation, indicating that DUB activity is essential for attenuating TLR signal transduction. Our combined results show that EBV employs deubiquitination of signaling intermediates in the TLR cascade as a mechanism to counteract innate anti-viral immunity of infected hosts.
Assuntos
Infecções por Vírus Epstein-Barr/imunologia , Evasão da Resposta Imune/imunologia , Transdução de Sinais/imunologia , Receptores Toll-Like/imunologia , Proteínas Virais Reguladoras e Acessórias/imunologia , Ensaio de Imunoadsorção Enzimática , Infecções por Vírus Epstein-Barr/metabolismo , Citometria de Fluxo , Imunofluorescência , Herpesvirus Humano 4 , Humanos , Imunidade Inata , Immunoblotting , Receptores Toll-Like/metabolismo , Transfecção , Proteínas Virais Reguladoras e Acessórias/metabolismoRESUMO
Active-site directed probes are powerful in studies of enzymatic function. We report an active-site directed probe based on a warhead so far considered unreactive. By replacing the C-terminal carboxylate of ubiquitin (Ub) with an alkyne functionality, a selective reaction with the active-site cysteine residue of de-ubiquitinating enzymes was observed. The resulting product was shown to be a quaternary vinyl thioether, as determined by X-ray crystallography. Proteomic analysis of proteins bound to an immobilized Ub alkyne probe confirmed the selectivity toward de-ubiquitinating enzymes. The observed reactivity is not just restricted to propargylated Ub, as highlighted by the selective reaction between caspase-1 (interleukin converting enzyme) and a propargylated peptide derived from IL-1ß, a caspase-1 substrate.
Assuntos
Alcinos/química , Cisteína/química , Peptídeo Hidrolases/metabolismo , Domínio CatalíticoAssuntos
Alopecia em Áreas/imunologia , Epitopos/isolamento & purificação , Autoantígenos/isolamento & purificação , Doenças Autoimunes/imunologia , Epitopos de Linfócito T/isolamento & purificação , Folículo Piloso/imunologia , Humanos , Mycobacterium tuberculosis/imunologia , Linfócitos T/imunologiaRESUMO
The appearance of group 1 CD1 proteins (CD1a, CD1b and CD1c) on maturing myeloid DC is a key event that converts myeloid DC to effective lipid APC. Here, we show that Borrelia burgdorferi, the causative agent of Lyme disease, triggers appearance of group 1 CD1 proteins at high density on the surface of human myeloid DC during infection. Within human skin, CD1b and CD1c expression was low or absent prior to infection, but increased significantly after experimental infections and in erythema migrans lesions from Lyme disease patients. The induction of CD1 was initiated by borrelial lipids acting through TLR-2 within minutes, but required 3 days for maximum effect. The delay in CD1 protein appearance involved a multi-step process whereby TLR-2 stimulated cells release soluble factors, which are sufficient to transfer the CD1-inducing effect in trans to other cells. Analysis of these soluble factors identified IL-1ß as a previously unknown pathway leading to group 1 CD1 protein function. This study establishes that upregulation of group 1 CD1 proteins is an early event in B. burgdorferi infection and suggests a stepwise mechanism whereby bacterial cell walls, TLR activation and cytokine release cause DC precursors to express group 1 CD1 proteins.
Assuntos
Antígenos CD1/metabolismo , Borrelia burgdorferi , Interleucina-1beta/metabolismo , Doença de Lyme/imunologia , Borrelia burgdorferi/imunologia , Células Dendríticas/imunologia , Eritema Migrans Crônico/imunologia , Glicoproteínas/metabolismo , Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Humanos , Técnicas In Vitro , Lipídeos/imunologia , Monócitos/efeitos dos fármacos , Monócitos/imunologia , Proteínas Recombinantes/farmacologia , Transdução de Sinais/imunologia , Pele/imunologia , Receptor 2 Toll-Like/metabolismo , Regulação para CimaRESUMO
Epitope-tagged active-site-directed probes are widely used to visualize the activity of deubiquitinases (DUBs) in cell extracts, to investigate the specificity and potency of small-molecule DUB inhibitors, and to isolate and identify DUBs by mass spectrometry. With DUBs arising as novel potential drug targets, probes are required that can be produced in sufficient amounts and to meet the specific needs of a given experiment. The established method for the generation of DUB probes makes use of labor-intensive intein-based methods that have inherent limitations concerning the incorporation of unnatural amino acids and the amount of material that can be obtained. Here, we describe the total chemical synthesis of active-site-directed probes and their application to activity-based profiling and identification of functional DUBs. This synthetic methodology allowed the easy incorporation of desired tags for specific applications, for example, fluorescent reporters, handles for immunoprecipitation or affinity pull-down, and cleavable linkers. Additionally, the synthetic method can be scaled up to provide significant amounts of probe. Fluorescent ubiquitin probes allowed faster, in-gel detection of active DUBs, as compared to (immuno)blotting procedures. A biotinylated probe holding a photocleavable linker enabled the affinity pull-down and subsequent mild, photorelease of DUBs. Also, DUB activity levels were monitored in response to overexpression or knockdown, and to inhibition by small molecules. Furthermore, fluorescent probes revealed differential DUB activity profiles in a panel of lung and prostate cancer cells.
Assuntos
Endopeptidases/metabolismo , Corantes Fluorescentes/química , Ubiquitina/química , Ubiquitina/metabolismo , Ubiquitinação , Biotina/química , Biotinilação , Domínio Catalítico , Linhagem Celular Tumoral , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/metabolismo , Humanos , Técnicas de Síntese em Fase SólidaAssuntos
Alopecia em Áreas/tratamento farmacológico , Piperidinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Pirróis/uso terapêutico , Adulto , Alopecia em Áreas/sangue , Biomarcadores/sangue , Feminino , Humanos , Piperidinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Pirróis/farmacologia , Pele/efeitos dos fármacos , Pele/metabolismoRESUMO
The high expression of CD1a on Langerhans cells in normal human skin suggests a central role for this lipid antigen presenting molecule in skin homeostasis and immunity. Although the lipid antigen presenting function of CD1a has been known for years, the physiological and pathological functions of the CD1a system in human skin remain incompletely understood. This review provides an overview of this active area of investigation, and discusses recent insights into the functions of CD1a, CD1a-restricted T cells, and lipid antigens in inflammatory and allergic skin disease. We include recent publications and work presented at the biennial CD1-MR1 EMBO workshop held in 2019 in Oxford, regarding lipids that increase and those that decrease T cell responses to CD1a.
Assuntos
Antígenos CD1/fisiologia , Dermatopatias/genética , Dermatopatias/imunologia , Apresentação de Antígeno/genética , Apresentação de Antígeno/imunologia , Humanos , Células de Langerhans/imunologia , Células de Langerhans/patologia , Ativação Linfocitária/genética , Pele/imunologia , Dermatopatias/patologia , Linfócitos T/imunologiaRESUMO
CD1a-autoreactive T cells contribute to skin disease, but the identity of immunodominant self-lipid antigens and their mode of recognition are not yet solved. In most models, MHC and CD1 proteins serve as display platforms for smaller antigens. Here, we showed that CD1a tetramers without added antigen stained large T cell pools in every subject tested, accounting for approximately 1% of skin T cells. The mechanism of tetramer binding to T cells did not require any defined antigen. Binding occurred with approximately 100 lipid ligands carried by CD1a proteins, but could be tuned upward or downward with certain natural self-lipids. TCR recognition mapped to the outer A' roof of CD1a at sites remote from the antigen exit portal, explaining how TCRs can bind CD1a rather than carried lipids. Thus, a major antigenic target of CD1a T cell autoreactivity in vivo is CD1a itself. Based on their high frequency and prevalence among donors, we conclude that CD1a-specific, lipid-independent T cells are a normal component of the human skin T cell repertoire. Bypassing the need to select antigens and effector molecules, CD1a tetramers represent a simple method to track such CD1a-specific T cells from tissues and in any clinical disease.