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1.
Nat Immunol ; 17(9): 1067-74, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27455421

RESUMO

The activating natural killer (NK)-cell receptor KIR3DS1 has been linked to the outcome of various human diseases, including delayed progression of disease caused by human immunodeficiency virus type 1 (HIV-1), yet a ligand that would account for its biological effects has remained unknown. We screened 100 HLA class I proteins and found that KIR3DS1 bound to HLA-F, a result we confirmed biochemically and functionally. Primary human KIR3DS1(+) NK cells degranulated and produced antiviral cytokines after encountering HLA-F and inhibited HIV-1 replication in vitro. Activation of CD4(+) T cells triggered the transcription and surface expression of HLA-F mRNA and HLA-F protein, respectively, and induced binding of KIR3DS1. HIV-1 infection further increased the transcription of HLA-F mRNA but decreased the binding of KIR3DS1, indicative of a mechanism for evading recognition by KIR3DS1(+) NK cells. Thus, we have established HLA-F as a ligand of KIR3DS1 and have demonstrated cell-context-dependent expression of HLA-F that might explain the widespread influence of KIR3DS1 in human disease.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Infecções por HIV/imunologia , HIV-1/fisiologia , Antígenos de Histocompatibilidade Classe I/metabolismo , Células Matadoras Naturais/imunologia , Receptores KIR3DS1/metabolismo , Citocinas/metabolismo , Citotoxicidade Imunológica , Progressão da Doença , Antígenos de Histocompatibilidade Classe I/genética , Humanos , Evasão da Resposta Imune , Células Jurkat , Ligantes , Ativação Linfocitária , Cultura Primária de Células , Receptores KIR3DS1/agonistas , Receptores KIR3DS1/genética , Latência Viral , Replicação Viral
2.
Proc Natl Acad Sci U S A ; 115(8): 1877-1882, 2018 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-29437954

RESUMO

HIV controllers (HCs) are individuals who can naturally control HIV infection, partially due to potent HIV-specific CD8+ T cell responses. Here, we examined the hypothesis that superior function of CD8+ T cells from HCs is encoded by their T cell receptors (TCRs). We compared the functional properties of immunodominant HIV-specific TCRs obtained from HLA-B*2705 HCs and chronic progressors (CPs) following expression in primary T cells. T cells transduced with TCRs from HCs and CPs showed equivalent induction of epitope-specific cytotoxicity, cytokine secretion, and antigen-binding properties. Transduced T cells comparably, albeit modestly, also suppressed HIV infection in vitro and in humanized mice. We also performed extensive molecular dynamics simulations that provided a structural basis for similarities in cytotoxicity and epitope cross-reactivity. These results demonstrate that the differential abilities of HIV-specific CD8+ T cells from HCs and CPs are not genetically encoded in the TCRs alone and must depend on additional factors.


Assuntos
Linfócitos T CD8-Positivos/fisiologia , Epitopos de Linfócito T/genética , Infecções por HIV/imunologia , HIV-1/imunologia , Receptores de Antígenos de Linfócitos T/genética , Clonagem Molecular , Regulação da Expressão Gênica/imunologia , Células HEK293 , Antígeno HLA-B27 , Humanos , Células Jurkat
3.
Nat Commun ; 14(1): 2929, 2023 05 22.
Artigo em Inglês | MEDLINE | ID: mdl-37217466

RESUMO

Cytotoxic-T-lymphocyte (CTL) mediated control of HIV-1 is enhanced by targeting highly networked epitopes in complex with human-leukocyte-antigen-class-I (HLA-I). However, the extent to which the presenting HLA allele contributes to this process is unknown. Here we examine the CTL response to QW9, a highly networked epitope presented by the disease-protective HLA-B57 and disease-neutral HLA-B53. Despite robust targeting of QW9 in persons expressing either allele, T cell receptor (TCR) cross-recognition of the naturally occurring variant QW9_S3T is consistently reduced when presented by HLA-B53 but not by HLA-B57. Crystal structures show substantial conformational changes from QW9-HLA to QW9_S3T-HLA by both alleles. The TCR-QW9-B53 ternary complex structure manifests how the QW9-B53 can elicit effective CTLs and suggests sterically hindered cross-recognition by QW9_S3T-B53. We observe populations of cross-reactive TCRs for B57, but not B53 and also find greater peptide-HLA stability for B57 in comparison to B53. These data demonstrate differential impacts of HLAs on TCR cross-recognition and antigen presentation of a naturally arising variant, with important implications for vaccine design.


Assuntos
Infecções por HIV , Humanos , Antígenos HLA-B/genética , Linfócitos T Citotóxicos , Peptídeos , Epitopos de Linfócito T , Receptores de Antígenos de Linfócitos T
4.
Rev Med Inst Mex Seguro Soc ; 52(5): 494-501, 2014.
Artigo em Espanhol | MEDLINE | ID: mdl-25301123

RESUMO

BACKGROUND: It is known that epinephrine/norepinephrine inhibit acute pain transmission. However, the role of ß-adrenoceptors is not clear. Thus, we analyzed if beta-1 and/or beta-2 adrenoceptors can modulate acute pain transmission by performing in vivo single unit recordings during painful and non-painful peripheral stimulation in rats. METHODS: Longitudinal study in which we analyzed seven groups of male rats Wistar: control group (n = 11): saline (0.9 %); EPI group (n = 8): epinephrine 100 mcg; beta-1 agonist group (n = 8): dobutamine 125 mcg; beta-1-antagonist group (n = 9): metoprolol 100 mcg; beta-2-agonist group (n = 7): clenbuterol 100 mcg; beta-2-antagonist group (n = 8): butoxamine 100 mcg; beta-1-antagonist + EPI group (n = 10): metoprolol 100 mcg + epinephrine 100 mcg. For the statistical analysis we used ANOVA. RESULTS: Epinephrine significantly reduced the basal firing rate (BFR) in 34.1 % (p < 0.05) and also the evoked response by painful stimulation in 56 % (p < 0.05). No change was observed in the evoked response by non-painful stimulation. ANTß1 was the only beta-adrenoceptor acting drug that significantly reduced the evoked response by painful stimulation in 41 % (p < 0.05). None of the other drugs alone affected either the BFR or the evoked response to non-painful or painful stimulation. CONCLUSIONS: It is the first time that a beta-1-adrenoceptor antagonist (metoprolol) probes to be effective in reducing the response to painful stimulation in WDR neurons.


Introducción: la epinefrina/norepinefrina inhibe la transmisión del dolor agudo; empero, no es claro el papel de los receptores beta-adrenérgicos. Por tanto, analizamos si los fármacos de estos receptores modulan la transmisión del dolor agudo mediante registro electrofisiológico unitario extracelular in vivo durante estimulación periférica dolorosa y no dolorosa en ratas. Métodos: estudio longitudinal en el que se cotejaron siete grupos de ratas: control (n = 11): solución salina (0,9 %); EPI (n = 8): 100 mcg epinefrina; agonista beta-1 (n = 8): 125 mcg dobutamina; antagonista beta-1 (n = 9): 100 mcg metoprolol; agonista beta-2 (n = 7): 100 mcg clembuterol; antagonista beta-2 (n = 8): butoxamina 100 mcg; antagonista beta-1 + EPI (n = 10): 100 mcg metoprolol + 100 mcg epinefrina. Se hizo análisis estadístico por medio de ANOVA. Resultados: La epinefrina redujo significativamente la tasa de disparo basal (RDB) en 34.1 % (p < 0.05) y la respuesta evocada por la estimulación dolorosa en 56 % (p < 0.05). No hubo cambios en la respuesta provocada por la falta de estimulación dolorosa. El antagonista beta-1 fue el único fármaco con acción beta-adrenérgica que redujo significativamente la respuesta evocada por la estimulación dolorosa en 41 % (p < 0.05). Conclusión: por primera vez un antagonista de los receptores beta-1-adrenérgicos (metoprolol) prueba ser eficaz en la reducción de la respuesta a la estimulación dolorosa en las neuronas ARD.


Assuntos
Antagonistas de Receptores Adrenérgicos beta 1/uso terapêutico , Metoprolol/uso terapêutico , Dor/tratamento farmacológico , Antagonistas de Receptores Adrenérgicos beta 1/farmacologia , Animais , Fenômenos Eletrofisiológicos/efeitos dos fármacos , Masculino , Metoprolol/farmacologia , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Estimulação Física , Ratos , Ratos Wistar , Medula Espinal
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