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1.
J Allergy Clin Immunol ; 151(6): 1595-1608.e6, 2023 06.
Artículo en Inglés | MEDLINE | ID: mdl-36708814

RESUMEN

BACKGROUND: On activation, mast cells rapidly release preformed inflammatory mediators from large cytoplasmic granules via regulated exocytosis. This acute degranulation is followed by a late activation phase involving synthesis and secretion of cytokines, growth factors, and other inflammatory molecules via the constitutive pathway that remains ill defined. OBJECTIVE: We investigated the role for an insulin-responsive vesicle-like endosomal compartment, marked by insulin-regulated aminopeptidase (IRAP), in the secretion of TNF-α and IL-6 in mast cells and macrophages. METHODS: Murine knockout (KO) mouse models (IRAP-KO and kit-Wsh/sh) were used to study inflammatory disease models and to measure and mechanistically investigate cytokine secretion and degranulation in bone marrow-derived mast cells in vitro. RESULTS: IRAP-KO mice are protected from TNF-α-dependent kidney injury and inflammatory arthritis. In the absence of IRAP, TNF-α and IL-6 but not IL-10 fail to be efficiently secreted. Moreover, chemical targeting of IRAP endosomes reduced proinflammatory cytokine secretion. Mechanistically, impaired TNF-α export from the Golgi and reduced colocalization of vesicle-associated membrane protein (VAMP) 3-positive TNF-α transport vesicles with syntaxin 4 (aka Stx4) was observed in IRAP-KO mast cells, while VAMP8-dependent exocytosis of secretory granules was facilitated. CONCLUSION: IRAP plays a novel role in mast cell-mediated inflammation through the regulation of exocytic trafficking of cytokines.


Asunto(s)
Aminopeptidasas , Citocinas , Ratones , Animales , Insulina , Mastocitos , Factor de Necrosis Tumoral alfa , Interleucina-6 , Inflamación
2.
Nat Immunol ; 10(6): 636-46, 2009 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-19412183

RESUMEN

Although cytotoxic T lymphocytes (CTLs) in people infected with human immunodeficiency virus type 1 can potentially target multiple virus epitopes, the same few are recognized repeatedly. We show here that CTL immunodominance in regions of the human immunodeficiency virus type 1 group-associated antigen proteins p17 and p24 correlated with epitope abundance, which was strongly influenced by proteasomal digestion profiles, affinity for the transporter protein TAP, and trimming mediated by the endoplasmatic reticulum aminopeptidase ERAAP, and was moderately influenced by HLA affinity. Structural and functional analyses demonstrated that proteasomal cleavage 'preferences' modulated the number and length of epitope-containing peptides, thereby affecting the response avidity and clonality of T cells. Cleavage patterns were affected by both flanking and intraepitope CTL-escape mutations. Our analyses show that antigen processing shapes CTL response hierarchies and that viral evolution modifies cleavage patterns and suggest strategies for in vitro vaccine optimization.


Asunto(s)
Presentación de Antígeno , Antígenos VIH/inmunología , Proteína p24 del Núcleo del VIH/inmunología , Linfocitos T Citotóxicos/inmunología , Productos del Gen gag del Virus de la Inmunodeficiencia Humana/inmunología , Transportadoras de Casetes de Unión a ATP/metabolismo , Secuencia de Aminoácidos , Evolución Molecular , Antígenos VIH/metabolismo , Proteína p24 del Núcleo del VIH/metabolismo , Infecciones por VIH/inmunología , Infecciones por VIH/virología , VIH-1/inmunología , Antígenos HLA-A/inmunología , Antígenos HLA-A/metabolismo , Humanos , Epítopos Inmunodominantes/genética , Epítopos Inmunodominantes/inmunología , Leucil Aminopeptidasa/metabolismo , Complejo Mayor de Histocompatibilidad , Modelos Moleculares , Datos de Secuencia Molecular , Mutación , Complejo de la Endopetidasa Proteasomal/inmunología , Complejo de la Endopetidasa Proteasomal/metabolismo , Unión Proteica , Linfocitos T Citotóxicos/virología , Productos del Gen gag del Virus de la Inmunodeficiencia Humana/metabolismo
3.
J Immunol ; 193(2): 901-8, 2014 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-24928998

RESUMEN

The endoplasmic reticulum aminopeptidases (ERAP)1 and ERAP2 play a critical role in the production of final epitopes presented by MHC class I molecules. Formation of heterodimers by ERAP1 and ERAP2 has been proposed to facilitate trimming of epitope precursor peptides, but the effects of dimerization on ERAP function remain unknown. In this study, we produced stabilized ERAP1-ERAP2 heterodimers and found that they produced several mature epitopes more efficiently than a mix of the two enzymes unable to dimerize. Physical interaction with ERAP2 changes basic enzymatic parameters of ERAP1 and improves its substrate-binding affinity. Thus, by bringing the two enzymes in proximity and by producing allosteric effects on ERAP1, dimerization of ERAP1/2 creates complexes with superior peptide-trimming efficacy. Such complexes are likely to enhance Ag presentation by cells displaying coordinated expression of the two enzymes.


Asunto(s)
Aminopeptidasas/inmunología , Epítopos/inmunología , Péptidos/inmunología , Multimerización de Proteína , Secuencia de Aminoácidos , Aminopeptidasas/genética , Aminopeptidasas/metabolismo , Animales , Presentación de Antígeno/inmunología , Células Cultivadas , Cromatografía Líquida de Alta Presión , Epítopos/metabolismo , Células HeLa , Humanos , Immunoblotting , Antígenos de Histocompatibilidad Menor , Datos de Secuencia Molecular , Péptidos/metabolismo , Unión Proteica/inmunología , Células Sf9 , Especificidad por Sustrato
4.
J Immunol ; 188(4): 1840-6, 2012 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-22238454

RESUMEN

Dendritic cells (DCs) use cellular pathways collectively referred to as cross-presentation to stimulate CD8(+) T cells with peptide Ags derived from internalized, exogenous Ags. We have recently reported that DCs rely on aminoterminal trimming of cross-presented peptides by insulin-responsive aminopeptidase (IRAP), an enzyme localized in a regulated endosomal storage compartment. Considering a report contending that this role is limited to inflammatory DCs (Segura et al. 2009. Proc. Natl. Acad. Sci. USA 106: 20377-20381), in this study, we examined the role of IRAP in steady-state DC subpopulations. Steady-state conventional DCs (cDCs) and plasmacytoid DCs expressed similar amounts of IRAP. IRAP colocalized with the endosomal markers Rab14 and syntaxin 6, both known to be associated with regulated endosomal storage compartments, in CD8(+) and CD8(-) cDCs-however, to a greater extent in the former population. Likewise, IRAP recruitment to phagosomes was significantly stronger in CD8(+) DCs. IRAP deficiency compromised cross-presentation of soluble and particulate Ag by both CD8(+) and CD8(-) cDCs, again with a stronger effect in the former population. Thus, the requirement of IRAP in cross-presentation extends to steady-state cDCs. Moreover, these data suggest that increased recruitment of an IRAP(+)/Rab14(+) compartment to Ag-containing vesicles contributes to the superior cross-presentation efficacy of CD8(+) cDCs.


Asunto(s)
Reactividad Cruzada , Cistinil Aminopeptidasa/metabolismo , Células Dendríticas/inmunología , Endosomas/inmunología , Proteínas de Unión al GTP rab/metabolismo , Animales , Presentación de Antígeno , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Células Cultivadas , Cistinil Aminopeptidasa/biosíntesis , Células Dendríticas/metabolismo , Endosomas/metabolismo , Ratones , Ratones Noqueados , Fagosomas/inmunología , Fagosomas/metabolismo , Proteínas Qa-SNARE/metabolismo
5.
Cell Rep ; 38(9): 110449, 2022 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-35235807

RESUMEN

Cytotoxic T lymphocyte (CTL) and natural killer (NK) cell responses to a single optimal 10-mer epitope (KK10) in the human immunodeficiency virus type-1 (HIV-1) protein p24Gag are associated with enhanced immune control in patients expressing human leukocyte antigen (HLA)-B∗27:05. We find that proteasomal activity generates multiple length variants of KK10 (4-14 amino acids), which bind TAP and HLA-B∗27:05. However, only epitope forms ≥8 amino acids evoke peptide length-specific and cross-reactive CTL responses. Structural analyses reveal that all epitope forms bind HLA-B∗27:05 via a conserved N-terminal motif, and competition experiments show that the truncated epitope forms outcompete immunogenic epitope forms for binding to HLA-B∗27:05. Common viral escape mutations abolish (L136M) or impair (R132K) production of KK10 and longer epitope forms. Peptide length influences how well the inhibitory NK cell receptor KIR3DL1 binds HLA-B∗27:05 peptide complexes and how intraepitope mutations affect this interaction. These results identify a viral escape mechanism from CTL and NK responses based on differential antigen processing and peptide competition.


Asunto(s)
Infecciones por VIH , VIH-1 , Secuencia de Aminoácidos , Aminoácidos , Presentación de Antígeno , Epítopos de Linfocito T , Antígenos HLA-B/genética , Humanos , Péptidos
6.
iScience ; 25(6): 104353, 2022 Jun 17.
Artículo en Inglés | MEDLINE | ID: mdl-35874918

RESUMEN

Targeting immune checkpoints, such as Programmed cell Death 1 (PD1), has improved survival in cancer patients by restoring antitumor immune responses. Most patients, however, relapse or are refractory to immune checkpoint blocking therapies. Neuropilin-1 (NRP1) is a transmembrane glycoprotein required for nervous system and angiogenesis embryonic development, also expressed in immune cells. We hypothesized that NRP1 could be an immune checkpoint co-receptor modulating CD8+ T cells activity in the context of the antitumor immune response. Here, we show that NRP1 is recruited in the cytolytic synapse of PD1+CD8+ T cells, cooperates and enhances PD-1 activity. In mice, CD8+ T cells specific deletion of Nrp1 improves anti-PD1 antibody antitumor immune responses. Likewise, in human metastatic melanoma, the expression of NRP1 in tumor infiltrating CD8+ T cells predicts poor outcome of patients treated with anti-PD1. NRP1 is a promising target to overcome resistance to anti-PD1 therapies.

7.
Front Cell Dev Biol ; 8: 585713, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33425891

RESUMEN

Dendritic cells (DCs) contribute to the immune surveillance by sampling their environment through phagocytosis and endocytosis. We have previously reported that, rapidly following uptake of extracellular antigen into phagosomes or endosomes in DCs, a specialized population of storage endosomes marked by Rab14 and insulin-regulated aminopeptidase (IRAP) is recruited to the nascent antigen-containing compartment, thereby regulating its maturation and ultimately antigen cross-presentation to CD8+ T lymphocytes. Here, using IRAP-/- DCs, we explored how IRAP modulates phagosome maturation dynamics and cross-presentation. We find that in the absence of IRAP, phagosomes acquire more rapidly late endosomal markers, are more degradative, and show increased microbicidal activity. We also report evidence for a role of vesicle trafficking from the endoplasmic reticulum (ER)-Golgi intermediate compartment to endosomes for the formation or stability of the IRAP compartment. Moreover, we dissect the dual role of IRAP as a trimming peptidase and a critical constituent of endosome stability. Experiments using a protease-dead IRAP mutant and pharmacological IRAP inhibition suggest that IRAP expression but not proteolytic activity is required for the formation of storage endosomes and for DC-typical phagosome maturation, whereas proteolysis is required for fully efficient cross-presentation. These findings identify IRAP as a key factor in cross-presentation, trimming peptides to fit the major histocompatibility complex class-I binding site while preventing their destruction through premature phagosome maturation.

8.
Nat Commun ; 11(1): 2779, 2020 06 02.
Artículo en Inglés | MEDLINE | ID: mdl-32487999

RESUMEN

T cell receptor (TCR) activation is modulated by mechanisms such as TCR endocytosis, which is thought to terminate TCR signalling. Here we show that, upon internalization, TCR continues to signal from a set of specialized endosomes that are crucial for T cell functions. Mechanistically, TCR ligation leads to clathrin-mediated internalization of the TCR-CD3ζ complex, while maintaining CD3ζ signalling, in endosomal vesicles that contain the insulin responsive aminopeptidase (IRAP) and the SNARE protein Syntaxin 6. Destabilization of this compartment through IRAP deletion enhances plasma membrane expression of the TCR-CD3ζ complex, yet compromises overall CD3ζ signalling; moreover, the integrity of this compartment is also crucial for T cell activation and survival after suboptimal TCR activation, as mice engineered with a T cell-specific deletion of IRAP fail to develop efficient polyclonal anti-tumour responses. Our results thus reveal a previously unappreciated function of IRAP-dependent endosomal TCR signalling in T cell activation.


Asunto(s)
Cistinil Aminopeptidasa/metabolismo , Endosomas/metabolismo , Receptores de Antígenos de Linfocitos T/metabolismo , Transducción de Señal/fisiología , Linfocitos T/metabolismo , Animales , Membrana Celular/metabolismo , Proliferación Celular , Clatrina/metabolismo , Cistinil Aminopeptidasa/genética , Modelos Animales de Enfermedad , Endocitosis/fisiología , Células HEK293 , Humanos , Interleucina-2/metabolismo , Activación de Linfocitos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas Qa-SNARE/metabolismo , Transcriptoma
9.
Methods Mol Biol ; 1988: 31-43, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31147930

RESUMEN

Studies over the last decade on characterization of the major histocompatibility complex (MHC) class I antigen presentation pathway have highlighted the importance of antigen processing, peptide transport, peptide trimming, and peptide selection as key stages for the development of optimal peptide repertoires that are presented by MHC class I molecules to cytotoxic T lymphocytes (CTLs). The study of these stages and how they are regulated, is fundamental for progress in understanding the adaptive immune system. Here we describe an in vitro assay monitoring peptide trimming by the human endoplasmic reticulum amino peptidases 1 (ERAP1) and ERAP2 (ERAPs) as a tool to characterize trimming events and gain a better understanding of the role and function of ERAPs in peptide repertoire development. Specifically, our assay allows for monitoring trimming of free but also of MHC I-bound peptides which may reflect the physiological situation best.


Asunto(s)
Aminopeptidasas/metabolismo , Antígenos de Histocompatibilidad Clase I/metabolismo , Antígenos de Histocompatibilidad Menor/metabolismo , Biología Molecular/métodos , Secuencia de Aminoácidos , Animales , Baculoviridae/metabolismo , Humanos , Ligandos , Péptidos/química , Péptidos/metabolismo , Multimerización de Proteína , Proteínas Recombinantes/metabolismo , Células Sf9
10.
Cell Rep ; 24(13): 3568-3581, 2018 09 25.
Artículo en Inglés | MEDLINE | ID: mdl-30257216

RESUMEN

Both cross-presentation of antigens by dendritic cells, a key pathway triggering T cell immunity and immune tolerance, and survival of several pathogens residing in intracellular vacuoles are intimately linked to delayed maturation of vesicles containing internalized antigens and microbes. However, how early endosome or phagosome identity is maintained is incompletely understood. We show that Toll-like receptor 4 (TLR4) and Fc receptor ligation induces interaction of the GTPase Rab14 with the kinesin KIF16b mediating plus-end-directed microtubule transport of endosomes. As a result, Rab14 recruitment to phagosomes delays their maturation and killing of an internalized pathogen. Enhancing anterograde transport by overexpressing Rab14, promoting the GTP-bound Rab14 state, or inhibiting retrograde transport upregulates cross-presentation. Conversely, reducing Rab14 expression, destabilizing Rab14 endosomes, and inhibiting anterograde microtubule transport by Kif16b knockdown compromise cross-presentation. Therefore, regulation of early endosome trafficking by innate immune signals is a critical parameter in cross-presentation by dendritic cells.


Asunto(s)
Reactividad Cruzada , Endosomas/metabolismo , Antígenos de Histocompatibilidad Clase I/inmunología , Inmunidad Innata , Animales , Células Cultivadas , Femenino , Cinesinas/metabolismo , Masculino , Ratones , Microtúbulos/metabolismo , Fagosomas/inmunología , Transporte de Proteínas , Receptores Fc/metabolismo , Receptor Toll-Like 4/metabolismo , Proteínas de Unión al GTP rab/metabolismo
11.
Sci Rep ; 6: 28902, 2016 08 12.
Artículo en Inglés | MEDLINE | ID: mdl-27514473

RESUMEN

The processing of MHC class I antigenic precursor peptides by the endoplasmic reticulum aminopeptidase 1 (ERAP1) and ERAP2 is an important event in the cell biology of antigen presentation. To date, the molecular context by which the ERAP enzymes trim precursor peptides, and how ERAPs shape peptide repertoires, remain open questions. Using ERAP1 and ERAP2 heterodimers (ERAP1/2), and N-terminally extended model and natural peptides in their free and HLA-B*0801-bound forms, we characterized the mode of action of ERAPs. We provide evidence that ERAP1/2 can trim MHC I-bound precursor peptides to their correct and final lengths, albeit more slowly than the corresponding free precursors. Trimming of MHC I-bound precursors by ERAP1/2 increases the conformational stability of MHC I/peptide complexes. From the data, we propose a molecular mechanistic model of ERAP1/2 as peptide editors. Overall, our study provides new findings on a significant issue of the ERAP-mediated processing pathway of MHC class I antigens.


Asunto(s)
Aminopeptidasas/química , Antígenos de Histocompatibilidad Clase I/química , Antígenos de Histocompatibilidad Menor/química , Péptidos/química , Dicroismo Circular , Disulfuros , Epítopos/química , Calor , Humanos , Modelos Moleculares , Unión Proteica , Dominios Proteicos , Multimerización de Proteína , Especificidad por Sustrato , Termolisina/química
12.
PLoS One ; 10(12): e0143883, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26624014

RESUMEN

Migration is crucial for the function of dendritic cells (DCs), which act as outposts of the immune system. Upon detection of pathogens, skin- and mucosa-resident DCs migrate to secondary lymphoid organs where they activate T cells. DC motility relies critically on the actin cytoskeleton, which is regulated by the actin-related protein 2/3 (ARP2/3) complex, a nucleator of branched actin networks. Consequently, loss of ARP2/3 stimulators and upstream Rho family GTPases dramatically impairs DC migration. However, nothing is known yet about the relevance of ARP2/3 inhibitors for DC migration. We previously demonstrated that the AP-1-associated adaptor protein Gadkin inhibits ARP2/3 by sequestering it on intracellular vesicles. Consistent with a role of Gadkin in DC physiology, we here report Gadkin expression in bone marrow-derived DCs and show that its protein level and posttranslational modification are regulated upon LPS-induced DC maturation. DCs derived from Gadkin-deficient mice were normal with regards to differentiation and maturation, but displayed increased actin polymerization. While the actin-dependent processes of macropinocytosis and cell spreading were not affected, loss of Gadkin significantly impaired DC migration in vitro, however, in vivo DC migration was unperturbed suggesting the presence of compensatory mechanisms.


Asunto(s)
Movimiento Celular/inmunología , Células Dendríticas/inmunología , Proteínas de la Membrana/metabolismo , Complejo 2-3 Proteico Relacionado con la Actina/inmunología , Complejo 2-3 Proteico Relacionado con la Actina/metabolismo , Actinas/inmunología , Actinas/metabolismo , Animales , Comunicación Celular/inmunología , Diferenciación Celular/inmunología , Células Dendríticas/metabolismo , Fenómenos del Sistema Inmunológico/inmunología , Activación de Linfocitos/inmunología , Proteínas de la Membrana/inmunología , Ratones , Ratones Endogámicos C57BL , Linfocitos T/inmunología , Linfocitos T/metabolismo , Factor de Transcripción AP-1/inmunología , Factor de Transcripción AP-1/metabolismo , Proteínas de Unión al GTP rho/inmunología , Proteínas de Unión al GTP rho/metabolismo
13.
Cell Rep ; 7(2): 448-463, 2014 Apr 24.
Artículo en Inglés | MEDLINE | ID: mdl-24726370

RESUMEN

The recent HIV-1 vaccine failures highlight the need to better understand virus-host interactions. One key question is why CD8(+) T cell responses to two HIV-Gag regions are uniquely associated with delayed disease progression only in patients expressing a few rare HLA class I variants when these regions encode epitopes presented by ~30 more common HLA variants. By combining epitope processing and computational analyses of the two HIV subtypes responsible for ~60% of worldwide infections, we identified a hitherto unrecognized adaptation to the antigen-processing machinery through substitutions at subtype-specific motifs. Multiple HLA variants presenting epitopes situated next to a given subtype-specific motif drive selection at this subtype-specific position, and epitope abundances correlate inversely with the HLA frequency distribution in affected populations. This adaptation reflects the sum of intrapatient adaptations, is predictable, facilitates viral subtype diversification, and increases global HIV diversity. Because low epitope abundance is associated with infrequent and weak T cell responses, this most likely results in both population-level immune evasion and inadequate responses in most people vaccinated with natural HIV-1 sequence constructs. Our results suggest that artificial sequence modifications at subtype-specific positions in vitro could refocus and reverse the poor immunogenicity of HIV proteins.


Asunto(s)
Adaptación Fisiológica , VIH-1/genética , Antígeno HLA-A1/genética , Evasión Inmune , Población/genética , África Austral , Secuencia de Aminoácidos , Epítopos/genética , Epítopos/inmunología , Europa (Continente) , Frecuencia de los Genes , Infecciones por VIH/epidemiología , Infecciones por VIH/genética , Infecciones por VIH/inmunología , VIH-1/inmunología , Antígeno HLA-A1/inmunología , Humanos , Datos de Secuencia Molecular , Linfocitos T/inmunología
14.
Methods Mol Biol ; 960: 351-357, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23329498

RESUMEN

In vitro cultures of bone marrow-derived precursors are a convenient method for generating dendritic cells (DC). This method additionally overcomes the problem of low availability of certain DC types, DC heterogeneity, and laborious procedures encountered using ex vivo isolation protocols.Here we describe two standard protocols for in vitro differentiation of steady-state DC equivalents with Fms-like tyrosine kinase 3 ligand (Flt3L) and inflammatory-like DC using granulocyte-macrophages-colony-stimulating factor (GM-CSF). These protocols allow for obtaining up to 2 × 10(8) CD11c(high) inflammatory-like DC and up to 5 × 10(6) equivalents of each CD8+ and CD8- conventional DC and plasmacytoid DC.


Asunto(s)
Técnicas de Cultivo de Célula/métodos , Células Dendríticas/citología , Animales , Células de la Médula Ósea/citología , Células de la Médula Ósea/efectos de los fármacos , Células Dendríticas/efectos de los fármacos , Factor Estimulante de Colonias de Granulocitos y Macrófagos/farmacología , Ligandos , Ratones , Tirosina Quinasa 3 Similar a fms/metabolismo
15.
Curr Opin Immunol ; 25(1): 90-6, 2013 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-23089230

RESUMEN

Peptides presented by MHC class I molecules are typically produced through antigen degradation by the proteasome followed by trimming by exopeptidases. According to recent results, these include both aminopeptidases and carboxypeptidases in the cytosol and the endoplasmic reticulum. While cytosolic peptidases have a net neutral or destructive effect on MHC ligands, endoplasmic reticulum aminopeptidases are required for efficient class I loading and have a strong effect on the repertoire of peptide/MHC complexes. Cells lacking these enzymes can be eliminated both by NK cells and by CD8+ T cells recognizing complexes formed between an MHC class Ib molecule and a conserved peptide. Cross-presented peptides derived from internalized antigens can be processed by insulin-regulated aminopeptidase, the only endosomal trimming peptidase.


Asunto(s)
Aminopeptidasas/inmunología , Carboxipeptidasas/inmunología , Retículo Endoplásmico/inmunología , Antígenos de Histocompatibilidad Clase I/inmunología , Complejo de la Endopetidasa Proteasomal/inmunología , Aminopeptidasas/genética , Animales , Carboxipeptidasas/genética , Reactividad Cruzada , Citotoxicidad Inmunológica/genética , Humanos , Células Asesinas Naturales/inmunología , Ligandos , Antígenos de Histocompatibilidad Menor , Fragmentos de Péptidos/inmunología , Fragmentos de Péptidos/metabolismo , Linfocitos T Citotóxicos/inmunología
16.
Science ; 325(5937): 213-7, 2009 Jul 10.
Artículo en Inglés | MEDLINE | ID: mdl-19498108

RESUMEN

Major histocompatibility complex (MHC) class I molecules present peptides, produced through cytosolic proteasomal degradation of cellular proteins, to cytotoxic T lymphocytes. In dendritic cells, the peptides can also be derived from internalized antigens through a process known as cross-presentation. The cellular compartments involved in cross-presentation remain poorly defined. We found a role for peptide trimming by insulin-regulated aminopeptidase (IRAP) in cross-presentation. In human dendritic cells, IRAP was localized to a Rab14+ endosomal storage compartment in which it interacted with MHC class I molecules. IRAP deficiency compromised cross-presentation in vitro and in vivo but did not affect endogenous presentation. We propose the existence of two pathways for proteasome-dependent cross-presentation in which final peptide trimming involves IRAP in endosomes and involves the related aminopeptidases in the endoplasmic reticulum.


Asunto(s)
Presentación de Antígeno , Reactividad Cruzada , Cistinil Aminopeptidasa/metabolismo , Células Dendríticas/inmunología , Endosomas/enzimología , Antígenos de Histocompatibilidad Clase I/inmunología , Antígenos de Histocompatibilidad Clase I/metabolismo , Traslado Adoptivo , Animales , Linfocitos T CD8-positivos/inmunología , Células Dendríticas/enzimología , Células Dendríticas/metabolismo , Epítopos , Antígenos HLA/inmunología , Antígenos HLA/metabolismo , Humanos , Ratones , Ratones Noqueados , Fagocitosis , Fagosomas/enzimología , Complejo de la Endopetidasa Proteasomal/metabolismo , Especificidad por Sustrato
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