title: Serine Phosphorylation of SLP76 Is Dispensable for T Cell Development but Modulates Helper T Cell Function.
abstract: The adapter protein SLP76 is a key orchestrator of T cell receptor (TCR) signal transduction. We previously identified a negative feedback loop that modulates T cell activation, involving phosphorylation of Ser376 of SLP76 by the hematopoietic progenitor kinase 1 (HPK1). However, the physiological relevance of this regulatory mechanism was still unknown. To address this question, we generated a SLP76-S376A-expressing knock-in mouse strain and investigated the effects of Ser376 mutation on T cell development and function. We report here that SLP76-S376A-expressing mice exhibit normal thymocyte development and no detectable phenotypic alterations in mature T cell subsets or other lymphoid and myeloid cell lineages. Biochemical analyses revealed that mutant T cells were hypersensitive to TCR stimulation. Indeed, phosphorylation of several signaling proteins, including SLP76 itself, phospholipase Cγ1 and the protein kinases AKT and ERK1/2, was increased. These modifications correlated with increased Th1-type and decreased Th2-type cytokine production by SLP76-S376A T cells, but did not result in significant changes of proliferative capacity nor activation-induced cell death susceptibility. Hence, our results reveal that SLP76-Ser376 phosphorylation does not mediate all HPK1-dependent regulatory effects in T cells but it fine-tunes helper T cell responses.
authors.affiliation: Lymphocyte Cell Biology Unit, Institut Pasteur, Paris, France.|CNRS URA 1961, Paris, France.|Université "Pierre et Marie Curie", Paris, France.
authors.forename: Victor H
authors.initials: VH
authors.lastname: Navas
authors.affiliation: Lymphocyte Cell Biology Unit, Institut Pasteur, Paris, France.|CNRS URA 1961, Paris, France.|INSERM U1221, Paris, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Cuche
authors.affiliation: Lymphocyte Cell Biology Unit, Institut Pasteur, Paris, France.|CNRS URA 1961, Paris, France.|INSERM U1221, Paris, France.
authors.forename: Andres
authors.initials: A
authors.lastname: Alcover
authors.affiliation: Lymphocyte Cell Biology Unit, Institut Pasteur, Paris, France.|CNRS URA 1961, Paris, France.|INSERM U1221, Paris, France.
authors.forename: Vincenzo
authors.identifier: http://orcid.org/0000-0002-5453-947X
authors.initials: V
authors.lastname: Di Bartolo
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D012694:Serine / Q000378:metabolism*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D010750:Phosphoproteins; C092947:SLP-76 signal Transducing adaptor proteins; D012694:Serine