title: Control of T cell antigen reactivity via programmed TCR downregulation.
abstract: The T cell antigen receptor (TCR) is unique in that its affinity for ligand is unknown before encounter and can vary by orders of magnitude. How the immune system regulates individual T cells that display very different reactivity to antigen remains unclear. Here we found that activated CD4(+) T cells, at the peak of clonal expansion, persistently downregulated their TCR expression in proportion to the strength of the initial antigen recognition. This programmed response increased the threshold for cytokine production and recall proliferation in a clone-specific manner and ultimately excluded clones with the highest antigen reactivity. Thus, programmed downregulation of TCR expression represents a negative feedback mechanism for constraining T cell effector function with a suitable time delay to thereby allow pathogen control while avoiding excess inflammatory damage.
authors.affiliation: Immunology Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
authors.forename: Alena M
authors.initials: AM
authors.lastname: Gallegos
authors.affiliation: Immunology Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
authors.forename: Huizhong
authors.initials: H
authors.lastname: Xiong
authors.affiliation: Immunology Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
authors.forename: Ingrid M
authors.initials: IM
authors.lastname: Leiner
authors.affiliation: Immunology Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
authors.forename: Bože
authors.initials: B
authors.lastname: Sušac
authors.affiliation: Immunology Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.|Infectious Diseases Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
authors.forename: Michael S
authors.identifier: http://orcid.org/0000-0001-7918-5164
authors.initials: MS
authors.lastname: Glickman
authors.affiliation: Immunology Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.|Infectious Diseases Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
authors.forename: Eric G
authors.initials: EG
authors.lastname: Pamer
authors.affiliation: Immunology Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
authors.forename: Jeroen W J
authors.identifier: http://orcid.org/0000-0002-8879-3521
authors.initials: JW
authors.lastname: van Heijst
mesh_terms: D000818:Animals; D000942:Antigens, Bacterial / Q000276:immunology; D001426:Bacterial Proteins / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D015536:Down-Regulation; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D015151:Immunoblotting; D008089:Listeria monocytogenes; D008088:Listeriosis / Q000276:immunology*; D008213:Lymphocyte Activation; D051379:Mice; D008822:Mice, Transgenic; D009169:Mycobacterium tuberculosis; D060888:Real-Time Polymerase Chain Reaction; D011948:Receptors, Antigen, T-Cell / Q000235:genetics* / Q000276:immunology; D013601:T-Lymphocytes; D018417:Th1 Cells / Q000276:immunology*; D059467:Transcriptome; D014397:Tuberculosis, Pulmonary / Q000276:immunology*
chemical_list: D000942:Antigens, Bacterial; D001426:Bacterial Proteins; C093276:ESAT-6 protein, Mycobacterium tuberculosis; D000949:Histocompatibility Antigens Class II; D011948:Receptors, Antigen, T-Cell