A THEMIS: SHP1 complex promotes T-cell survival

• Wolfgang Paster ^[1] ; Annika M Bruger ^[1] ; Kristin Katsch ^[1] ; Claude Grégoire ^[4] ; Romain Roncagalli ^[4] ; Guo Fu ^[2] ; Nicholas RJ Gascoigne ^[5] ; Konstantina Nika ^[1] ; Andre Cohnen ^[1] ; Stephan M Feller ^[3] ; Philip C Simister ^[3] ; Kelly C Molder ^[1] ; Shaun-Paul Cordoba ^[1] ; Omer Dushek ^[1] ; Bernard Malissen ^[4] ; Oreste Acuto ^[1]
  1. [1] University of Oxford

     University of Oxford

     Oxford District, Reino Unido

     
  2. [2] Scripps Research Institute

     Scripps Research Institute

     Estados Unidos

     
  3. [3] Weatherall Institute of Molecular Medicine

     Weatherall Institute of Molecular Medicine

     Oxford District, Reino Unido

     
  4. [4] 2 Centre d'Immunologie de Marseille-Luminy, UM2 Aix-Marseille Université Marseille, France; 3 INSERM U1104 Marseille, France; 4 CNRS UMR7280 Marseille, France
  5. [5] 5 Department of Immunology and Microbial Science, The Scripps Research Institute La Jolla, CA, USA; 6 Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore Singapore, Singapore

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• Localización: EMBO journal: European Molecular Biology Organization, ISSN 0261-4189, Vol. 34, Nº. 3, 2014, págs. 393-409
• Idioma: inglés
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  • THEMIS is critical for conventional T-cell development, but its precise molecular function remains elusive. Here, we show that THEMIS constitutively associates with the phosphatases SHP1 and SHP2. This complex requires the adapter GRB2, which bridges SHP to THEMIS in a Tyr-phosphorylation-independent fashion. Rather, SHP1 and THEMIS engage with the N-SH3 and C-SH3 domains of GRB2, respectively, a configuration that allows GRB2-SH2 to recruit the complex onto LAT. Consistent with THEMIS-mediated recruitment of SHP to the TCR signalosome, THEMIS knock-down increased TCR-induced CD3-ζ phosphorylation, Erk activation and CD69 expression, but not LCK phosphorylation. This generalized TCR signalling increase led to augmented apoptosis, a phenotype mirrored by SHP1 knock-down. Remarkably, a KI mutation of LCK Ser59, previously suggested to be key in ERK-mediated resistance towards SHP1 negative feedback, did not affect TCR signalling nor ligand discrimination in vivo. Thus, the THEMIS:SHP complex dampens early TCR signalling by a previously unknown molecular mechanism that favours T-cell survival. We discuss possible implications of this mechanism in modulating TCR output signals towards conventional T-cell development and differentiation.