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Sci Immunol. 2019 Feb 15;4(32). pii: eaal2201. doi: 10.1126/sciimmunol.aal2201.

The early proximal αβ TCR signalosome specifies thymic selection outcome through a quantitative protein interaction network.

Author information

1
Department of Immunology, Mayo Clinic College of Medicine, Rochester, MN, USA.
2
Mayo Graduate School, Mayo Clinic College of Medicine, Rochester, MN, USA.
3
Medical Scientist Training Program, Mayo Clinic College of Medicine, Rochester, MN, USA.
4
Department of Neurology, Mayo Clinic College of Medicine, Rochester, MN, USA.
5
Molecular Pathogenesis and Therapeutics PhD Graduate Program, University of Missouri, Columbia, MO, USA.
6
Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Victoria 3010, Australia.
7
QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4006, Australia.
8
School of Medicine, University of Queensland, Brisbane, Queensland 4006, Australia.
9
Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia.
10
ARC Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, Victoria 3800, Australia.
11
Institute of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, UK.
12
Thoracic Diseases Research Unit, Division of Pulmonary Critical Care and Internal Medicine, Mayo Clinic College of Medicine, Rochester, MN, USA.
13
Blood Cell Development and Cancer Keystone, Immune Cell Development and Host Defense Program, Fox Chase Cancer Center, Philadelphia, PA, USA.
14
Department of Surgery, Mayo Clinic College of Medicine, Rochester, MN, USA.
15
Department of Molecular Microbiology and Immunology, School of Medicine, University of Missouri, Columbia, MO, USA.
16
Department of Surgery, School of Medicine, University of Missouri, Columbia, MO, USA.
17
University of Minnesota Informatics Institute, Minneapolis, MN, USA.
18
Department of Molecular Microbiology and Immunology, School of Medicine, University of Missouri, Columbia, MO, USA. schruma@health.missouri.edu gilpagesd@health.missouri.edu.
19
Department of Bioengineering, College of Engineering, University of Missouri, Columbia, MO, USA.

Abstract

During αβ T cell development, T cell antigen receptor (TCR) engagement transduces biochemical signals through a protein-protein interaction (PPI) network that dictates dichotomous cell fate decisions. It remains unclear how signal specificity is communicated, instructing either positive selection to advance cell differentiation or death by negative selection. Early signal discrimination might occur by PPI signatures differing qualitatively (customized, unique PPI combinations for each signal), quantitatively (graded amounts of a single PPI series), or kinetically (speed of PPI pathway progression). Using a novel PPI network analysis, we found that early TCR-proximal signals distinguishing positive from negative selection appeared to be primarily quantitative in nature. Furthermore, the signal intensity of this PPI network was used to find an antigen dose that caused a classic negative selection ligand to induce positive selection of conventional αβ T cells, suggesting that the quantity of TCR triggering was sufficient to program selection outcome. Because previous work had suggested that positive selection might involve a qualitatively unique signal through CD3δ, we reexamined the block in positive selection observed in CD3δ0 mice. We found that CD3δ0 thymocytes were inhibited but capable of signaling positive selection, generating low numbers of MHC-dependent αβ T cells that expressed diverse TCR repertoires and participated in immune responses against infection. We conclude that the major role for CD3δ in positive selection is to quantitatively boost the signal for maximal generation of αβ T cells. Together, these data indicate that a quantitative network signaling mechanism through the early proximal TCR signalosome determines thymic selection outcome.

PMID:
30770409
DOI:
10.1126/sciimmunol.aal2201

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