Identificacion de los dominios de CD3-'eta' implicados en endocitosis y ensamblaje

Centro de Informacion y Documentacion Cientifica (CINDOC). C/Joaquin Costa, 22. 28002 Madrid. SPAIN / CINDOC - Centro de Informaciòn y Documentaciòn CientìficaSIGLEESSpai

A non-conserved amino acid variant regulates differential signalling between human and mouse CD28

CD28 superagonistic antibodies (CD28SAb) can preferentially activate and expand immunosuppressive regulatory T cells (Treg) in mice. However, pre-clinical trials assessing CD28SAbs for the therapy of autoimmune diseases reveal severe systemic inflammatory response syndrome in humans, thereby implying the existence of distinct signalling abilities between human and mouse CD28. Here, we show that a single amino acid variant within the C-terminal proline-rich motif of human and mouse CD28 (P in human vs. A in mouse) regulates CD28-induced NF-κB activation and pro-inflammatory cytokine gene expression. Moreover, this YAPP sequence in humans is crucial for the association of CD28 with the Nck adaptor protein for actin cytoskeleton reorganisation events necessary for CD28 autonomous signalling. This study thus unveils different outcomes between human and mouse CD28 signalling to underscore the importance of species difference when transferring results from preclinical models to the bedside.Progetto Ateneo” (Sapienza University of Rome, Italy) and Multiple Sclerosis Italian Foundation (FISM 2016/R/29)Peer Reviewe

1H-NMR analysis of CD3-ε reveals the presence of turnhelix structures around the itam motif in an otherwise random coil cytoplasmic tail

The conformation adopted in solution by the cytoplasmic tail of CD3-B has been analyzed by 'H-nmr. Tlie cytoplasmic tail is mostly random coil except for the amino acids conforming the imimmoreceptor tyrosine-based activation motif (ITAM), YxxL/IxxxxxxxYxxL. Although the N-terminal YxxL sequence of the motif is poorly folded, adopting 6-residue turn-like conformations with the Tyr side chain in t\vo different orientations, the C-tenninal YxxL sequence is placed in a more complex structure involving a set of nonclassical a-helix turns and -tums that comprises 11 amino acids. Tills st met lire is not modified by phosphorylation of the tyrosine residue. Tlie differences in the conformation adopted around the t\vo tyrosines of the ITAM motif suggest that they may play different roles pertaining to either binding signal transducing proteins or, alternatively, proteins involved in other processes such as endoplasmic reticulum location. ©1997 John Wiley & Sons, Inc.This work was supported by grants from CICYT PM95-0005, Comunidad de Madrid (AE13/95) , the European Union Biotech Program (BIOCT920164) , the Fundación Rodríguez Pascual, and Fundación Ramón Areces.Peer Reviewe

Inmunosupresor basado en la interrupción de la interacción TCR-Nck

[EN] The invention relates to a compound of structural formula (1) and the derivatives thereof, for the use thereof as a medicament, preferably as an immunosuppressive agent based on the interruption of TCR-Nck interaction.[ES] La presente invención se refiere a un compuesto de fórmula estructural (1) y sus derivados, para su uso como medicamento. Preferiblemente como agente inmunosupresor basado en la interrupción de la interacción TCR-Nck.Peer reviewedConsejo Superior de Investigaciones Científicas (España)A1 Solicitud de patentes con informe sobre el estado de la técnic

Nck Recruitment to the TCR required for ZAP70 activation during thymic development

et al.The adaptor protein Nck is inducibly recruited through its SH3.1 domain to a proline-rich sequence (PRS) in CD3 after TCR engagement. However, experiments with a knockin mutant bearing an 8-aa replacement of the PRS have indicated that Nck binding to the TCR is constitutive, and that it promotes the degradation of the TCR in preselection double-positive (DP) CD4+ CD8+ thymocytes. To clarify these discrepancies, we have generated a new knockin mouse line (KI-PRS) bearing a conservative mutation in the PRS resulting from the replacement of the two central prolines. Thymocytes of KI-PRS mice are partly arrested at each step at which pre-TCR or TCR signaling is required. The mutation prevents the trigger-dependent inducible recruitment of endogenous Nck to the TCR but does not impair TCR degradation. However, KI-PRS preselection DP thymocytes show impaired tyrosine phosphorylation of CD3z, as well as impaired recruitment of ZAP70 to the TCR and impaired ZAP70 activation. Our results indicate that Nck is recruited to the TCR in an inducible manner in DP thymocytes, and that this recruitment is required for the activation of early TCR-dependent events. Differences in the extent of PRS mutation could explain the phenotypic differences in both knockin mice. Copyright © 2013 by The American Association of Immunologists, Inc.Comision Interministerial de Ciencia y Tecnologia (Grant SAF2010-14912); Redes Temáticas de Investigación Cooperativa Sanitaria (Grant RD06/0020/1002); Fundación Científica Asociación Española Contra el Cáncer; European Union (Grant FP7/2007-2013 “SYBILLA”); Deutsche Forschungsgemeinschaft (Grant SFB620); Bundesministerium fur Bildung; Wissenschaft, Forschung und Technologie (Grant 01 EO 0803); Fundación Ramón Areces.Peer Reviewe

Conventional CD4+ T cells present bacterial antigens to induce cytotoxic and memory CD8+ T cell responses

Bacterial phagocytosis and antigen cross-presentation to activate CD8 T cells are principal functions of professional antigen presenting cells. However, conventional CD4 T cells also capture and kill bacteria from infected dendritic cells in a process termed transphagocytosis (also known as transinfection). Here, we show that transphagocytic T cells present bacterial antigens to naive CD8 T cells, which proliferate and become cytotoxic in response. CD4 T-cell-mediated antigen presentation also occurs in vivo in the course of infection, and induces the generation of central memory CD8 T cells with low PD-1 expression. Moreover, transphagocytic CD4 T cells induce protective anti-tumour immune responses by priming CD8 T cells, highlighting the potential of CD4 T cells as a tool for cancer immunotherapy.Spanish Ministries of Science and Technology (MICINN; BFU2011-29450 to E.V.) and of Economy and Competitiveness (MINECO; SAF2014-56716-REDT and BFU2014-59585-R to E.V., SAF2014-55579-R to F.S.M., SAF2013-47975-R to B.A., SAF2014-58895-JIN to A.C.-A.), the ISCIII (PI14/00526; CP11/00145; CPII16/00022 to J.M.G.-G.), the Fundación Ramón Areces (to J.M.G.-G.), the Madrid regional government (INDISNET-S2011/BMD-2332 to F.S.M.) and the European Research Council (ERC-2011-AdG 294340-GENTRIS to F.S.M.; ERC 2013-AdG 334763 NOVARIPP to B.A.)Peer Reviewe

Dynamic reorganisation of intermediate filaments coordinates early B-cell activation

During B-cell activation, the dynamic reorganisation of the cytoskeleton is crucial for multiple cellular responses, such as receptor signalling, cell spreading, antigen internalisation, intracellular trafficking, and antigen presentation. However, the role of intermediate filaments (IFs), which represent a major component of the mammalian cytoskeleton, is not well defined. Here, by using multiple super-resolution microscopy techniques, including direct stochastic optical reconstruction microscopy, we show that IFs in B cells undergo drastic reorganisation immediately upon antigen stimulation and that this reorganisation requires actin and microtubules. Although the loss of vimentin in B cells did not impair B-cell development, receptor signalling, and differentiation, vimentin-deficient B cells exhibit altered positioning of antigen-containing and lysosomal associated membrane protein 1 (LAMP1) compartments, implying that vimentin may play a role in the fine-tuning of intracellular trafficking. Indeed, vimentin-deficient B cells exhibit impaired antigen presentation and delayed antibody responses in vivo. Thus, our study presents a new perspective on the role of IFs in B-cell activation.Francis Crick Institute core funded by Cancer Research UK (FC001035 and FC001136), the UK Medical Research Council (FC001035 and FC001136),Peer Reviewe

Derivados de cromeno

[EN The invention relates to chromene derivatives having formula (1), the significance of the various substituents being provided in the description. These compounds can be used as inhibitors of the TCRNkc interaction in T-lymphocytes.[ES] Derivados de cromeno de fórmula (1), donde los significados para los distintos sustituyentes son los indicados en la descripción. Estos compuestos son útiles como inhibidores de la interacción TCR-Nkc en linfocitos T.Peer reviewedConsejo Superior de Investigaciones CientíficasA1 Solicitud de patente con informe sobre el estado de la técnic

CD3 epsilon recruits Numb to promote TCR degradation

Modulation of TCR signaling upon ligand binding is achieved by changes in the equilibrium between TCR degradation, recycling and synthesis; surprisingly, the molecular mechanism of such an important process is not fully understood. Here, we describe the role of a new player in the mediation of TCR degradation: the endocytic adaptor Numb. Our data show that Numb inhibition leads to abnormal intracellular distribution and defective TCR degradation in mature T lymphocytes. In addition, we find that Numb simultaneously binds to both Cbl and a site within CD3 epsilon that overlaps with the Nck binding site. As a result, Cbl couples specifically to the CD3 epsilon chain to mediate TCR degradation. The present study unveils a novel role of Numb that lies at the heart of TCR signaling initiation and termination.The work was funded by grants BFU2004-01771, BFU2007-67476 and BFU2010-21634 from the Spanish Science and Education Ministry, a Special Intramural CSIC (Spanish Science Council) grant and the Excellence grant P06-CTS-02112 from the Department of Science and Innovation of the Regional Government of Andalucia, Spain (M.C.), and grants SAF08-01581 and RD06/0020/0017 (J.L.).Peer reviewe

Antigen presentation between T cells drives Th17 polarization under conditions of limiting antigen

T cells form immunological synapses with professional antigen-presenting cells (APCs) resulting in T cell activation and the acquisition of peptide antigen-MHC (pMHC) complexes from the plasma membrane of the APC. They thus become APCs themselves. We investigate the functional outcome of T-T cell antigen presentation by CD4 T cells and find that the antigen-presenting T cells (Tpres) predominantly differentiate into regulatory T cells (Treg), whereas T cells that have been stimulated by Tpres cells predominantly differentiate into Th17 pro-inflammatory cells. Using mice deficient in pMHC uptake by T cells, we show that T-T antigen presentation is important for the development of experimental autoimmune encephalitis and Th17 cell differentiation in vivo. By varying the professional APC:T cell ratio, we can modulate Treg versus Th17 differentiation in vitro and in vivo, suggesting that T-T antigen presentation underlies proinflammatory responses in conditions of antigen scarcity.This work was funded by grant no. SAF2016-76394-R, from the CICYT, by grant no. S2017/BMD-3671 from the Comunidad de Madrid, and by the European Research Council ERC 2013-Advanced Grant 334763 “NOVARIPP” (to B.A.). V.L.B. was supported by an ITN-Marie Curie Fellowship. CBMSO acknowledges the support of the Fundación Ramón Areces