Themis sets the signal threshold for positive and negative selection in T-cell development.
Development of a self-tolerant T-cell receptor (TCR) repertoire with the potential to recognize the universe of infectious agents depends on proper regulation of TCR signalling. The repertoire is whittled down during T-cell development in the thymus by the ability of quasi-randomly generated TCRs to interact with self-peptides presented by major histocompatibility complex (MHC) proteins. Low-affinity TCR interactions with self-MHC proteins generate weak signals that initiate 'positive selection', causing maturation of CD4- or CD8αβ-expressing 'single-positive' thymocytes from CD4(+)CD8αβ(+) 'double-positive' precursors. These develop into mature naive T cells of the secondary lymphoid organs. TCR interaction with high-affinity agonist self-ligands results in 'negative selection' by activation-induced apoptosis or 'agonist selection' of functionally differentiated self-antigen-experienced T cells. Here we show that positive selection is enabled by the ability of the T-cell-specific protein Themis to specifically attenuate TCR signal strength via SHP1 recruitment and activation in response to low- but not high-affinity TCR engagement. Themis acts as an analog-to-digital converter translating graded TCR affinity into clear-cut selection outcome. By dampening mild TCR signals Themis increases the affinity threshold for activation, enabling positive selection of T cells with a naive phenotype in response to low-affinity self-antigens.
Department of Immunology and Microbial Science, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
Guo
G
Fu
1] Department of Immunology and Microbial Science, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA [2] Department of Microbiology, Yong Loo Lin School of Medicine and Immunology Programme, National University of Singapore, 5 Science Drive 2, Singapore 117545 [3].
Javier
J
Casas
1] Department of Immunology and Microbial Science, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA [2].
Stephanie
S
Rigaud
1] Department of Immunology and Microbial Science, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA [2] Department of Microbiology, Yong Loo Lin School of Medicine and Immunology Programme, National University of Singapore, 5 Science Drive 2, Singapore 117545 [3].
Vasily
V
Rybakin
Developmental Immunology, La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, California 92037, USA.
Florence
F
Lambolez
1] Department of Immunology and Microbial Science, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA [2] Department of Microbiology, Yong Loo Lin School of Medicine and Immunology Programme, National University of Singapore, 5 Science Drive 2, Singapore 117545.
Joanna
J
Brzostek
Department of Immunology and Microbial Science, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
John A H
JA
Hoerter
Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK.
Wolfgang
W
Paster
Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK.
Oreste
O
Acuto
Developmental Immunology, La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, California 92037, USA.
Hilde
H
Cheroutre
1] Department of Immunology and Microbial Science, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA [2] Department of Cell and Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
Karsten
K
Sauer
1] Department of Immunology and Microbial Science, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA [2] Department of Microbiology, Yong Loo Lin School of Medicine and Immunology Programme, National University of Singapore, 5 Science Drive 2, Singapore 117545.
Nicholas R J
NR
Gascoigne
D000818:Animals; D017209:Apoptosis; D001324:Autoantigens / Q000276:immunology; D020013:Calcium Signaling; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000166:cytology* / Q000276:immunology / Q000378:metabolism*; D060168:Thymocytes / Q000166:cytology* / Q000276:immunology / Q000378:metabolism*
D001324:Autoantigens; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D011506:Proteins; D011948:Receptors, Antigen, T-Cell; C544192:themis protein, mouse; D048049:Extracellular Signal-Regulated MAP Kinases; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6