RESUMO
Formation of the immunological synapse between an antigen-presenting cell (APC) and a T cell leads to signal generation in both cells involved. In T cells, the lipid raft-associated transmembrane adaptor protein LAT plays a central role. Its phosphorylation is a crucial step in signal propagation, including the calcium response and mitogen-activated protein kinase activation, and largely depends on its association with the SLP76 adaptor protein. Here we report the discovery of a new palmitoylated transmembrane adaptor protein, termed SCIMP. SCIMP is expressed in B cells and other professional APCs and is localized in the immunological synapse due to its association with tetraspanin-enriched microdomains. In B cells, it is constitutively associated with Lyn kinase and becomes tyrosine phosphorylated after major histocompatibility complex type II (MHC-II) stimulation. When phosphorylated, SCIMP binds to the SLP65 adaptor protein and also to the inhibitory kinase Csk. While the association with SLP65 initiates the downstream signaling cascades, Csk binding functions as a negative regulatory loop. The results suggest that SCIMP is involved in signal transduction after MHC-II stimulation and therefore serves as a regulator of antigen presentation and other APC functions.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Células Apresentadoras de Antígenos/imunologia , Antígenos de Histocompatibilidade Classe II/imunologia , Proteínas de Membrana/metabolismo , Fosfoproteínas/metabolismo , Linfócitos T/imunologia , Proteínas Adaptadoras de Transdução de Sinal/química , Sequência de Aminoácidos , Apresentação de Antígeno , Linfócitos B/imunologia , Linfócitos B/metabolismo , Proteína Tirosina Quinase CSK , Células HEK293 , Antígenos de Histocompatibilidade Classe II/metabolismo , Humanos , Sinapses Imunológicas/química , Ativação Linfocitária , Microdomínios da Membrana/química , Microdomínios da Membrana/metabolismo , Proteínas de Membrana/química , Proteínas de Membrana/genética , Proteínas de Membrana/imunologia , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Dados de Sequência Molecular , Proteínas Tirosina Quinases/química , Proteínas Tirosina Quinases/metabolismo , Interferência de RNA , RNA Interferente Pequeno , Transdução de Sinais , Domínios de Homologia de src , Quinases da Família src/metabolismoRESUMO
A 31-year-old Chinese man with intractable severe, lifelong Tourette's syndrome characterised by forceful self-injurious motor tics and socially embarrassing vocal tics was treated with bilateral deep brain stimulation. Electrodes were implanted into the thalamic targets at the centromedian-parafascicular complex according to Hassler's nomenclature. A dramatic reduction of tics resulted. At 18 months postoperatively, there was an 81% improvement in his total tics count and a 58% improvement in his Yale Global Tic Severity Scale. His modified Rush video scale decreased from 13 to 8 and visual analogue scale from 10 to 3. These data show that bilateral deep brain stimulation of the thalamus can have a favourable immediate effect on severe tics in a selected group of adult patients suffering from intractable Tourette's syndrome and postoperatively the beneficial effects persisted for at least 18 months.
Assuntos
Estimulação Encefálica Profunda/métodos , Síndrome de Tourette/terapia , Adulto , Humanos , Masculino , Síndrome de Tourette/fisiopatologiaRESUMO
Krüppel-like factor 2 (KLF2) is a member of zinc-finger transcription factors. Based on its expression in naive and memory T cells and the activated phenotype of few T cells in mice lacking KLF2 in the lymphoid lineage, KLF2 is postulated to regulate T cell homeostasis by promoting cell quiescence. In this study, we show that in reporter gene assays KLF2 directly activates the promoters of both CD62L and sphingosine-1-phosphate receptor 1 (S1P1), whose expression is critical for T cell egress from the thymus and homing to the lymph nodes. Correspondingly, exogenous KLF2 expression in primary T cells significantly up-regulates both CD62L and S1P1. Following adoptive transfer, KLF2-transduced T cells are much more efficient in homing to lymphoid organs than nontransduced T cells. These findings suggest that KLF2 regulates T cell homeostasis at least partly by controlling CD62L and S1P1 expression, and therefore T cell egress from the thymus and circulation in the periphery.