title: The lymphoid lineage-specific actin-uncapping protein Rltpr is essential for costimulation via CD28 and the development of regulatory T cells.
abstract: Although T cell activation can result from signaling via T cell antigen receptor (TCR) alone, physiological T cell responses require costimulation via the coreceptor CD28. Through the use of an N-ethyl-N-nitrosourea-mutagenesis screen, we identified a mutation in Rltpr. We found that Rltpr was a lymphoid cell-specific, actin-uncapping protein essential for costimulation via CD28 and the development of regulatory T cells. Engagement of TCR-CD28 at the immunological synapse resulted in the colocalization of CD28 with both wild-type and mutant Rltpr proteins. However, the connection between CD28 and protein kinase C-θ and Carma1, two key effectors of CD28 costimulation, was abrogated in T cells expressing mutant Rltpr, and CD28 costimulation did not occur in those cells. Our findings provide a more complete model of CD28 costimulation in which Rltpr has a key role.
authors.affiliation: Centre d'Immunologie de Marseille-Luminy, Aix Marseille Université, Marseille, France.
authors.forename: Yinming
authors.initials: Y
authors.lastname: Liang
authors.forename: Margot
authors.initials: M
authors.lastname: Cucchetti
authors.forename: Romain
authors.initials: R
authors.lastname: Roncagalli
authors.forename: Tadashi
authors.initials: T
authors.lastname: Yokosuka
authors.forename: Aurélie
authors.initials: A
authors.lastname: Malzac
authors.forename: Elodie
authors.initials: E
authors.lastname: Bertosio
authors.forename: Jean
authors.initials: J
authors.lastname: Imbert
authors.forename: Isaac J
authors.initials: IJ
authors.lastname: Nijman
authors.forename: Miloslav
authors.initials: M
authors.lastname: Suchanek
authors.forename: Takashi
authors.initials: T
authors.lastname: Saito
authors.forename: Christoph
authors.initials: C
authors.lastname: Wülfing
authors.forename: Bernard
authors.initials: B
authors.lastname: Malissen
authors.forename: Marie
authors.initials: M
authors.lastname: Malissen
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D053468:CARD Signaling Adaptor Proteins / Q000276:immunology*; D018106:CD28 Antigens / Q000276:immunology*; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology*; D005434:Flow Cytometry; D006162:Guanylate Cyclase / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008840:Microfilament Proteins; D018613:Microscopy, Confocal; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D011493:Protein Kinase C / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA; D013047:Specific Pathogen-Free Organisms; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D053468:CARD Signaling Adaptor Proteins; C547525:CARMIL1 protein, human; D018106:CD28 Antigens; D002352:Carrier Proteins; D008840:Microfilament Proteins; D011948:Receptors, Antigen, T-Cell; D011493:Protein Kinase C; C426242:CARD11 protein, human; D006162:Guanylate Cyclase