@article{ad72231bea164b88bacd7ea8b7a55077,
title = "Dynamics of the Coreceptor-LCK Interactions during T Cell Development Shape the Self-Reactivity of Peripheral CD4 and CD8 T Cells",
abstract = "Overtly self-reactive T cells are removed during thymic selection. However, it has been recently established that T cell self-reactivity promotes protective immune responses. Apparently, the level of self-reactivity of mature T cells must be tightly balanced. Our mathematical model and experimental data show that the dynamic regulation of CD4- and CD8-LCK coupling establish the self-reactivity of the peripheral T cell pool. The stoichiometry of the interaction between CD8 and LCK, but not between CD4 and LCK, substantially increases upon T cell maturation. As a result, peripheral CD8+ T cells are more self-reactive than CD4+ T cells. The different levels of self-reactivity of mature CD8+ and CD4+ T cells likely reflect the unique roles of these subsets in immunity. These results indicate that the evolutionary selection pressure tuned the CD4-LCK and CD8-LCK stoichiometries, as they represent the unique parts of the proximal T cell receptor (TCR) signaling pathway, which differ between CD4+ and CD8+ T cells.",
keywords = "CD4, CD8, evolution of the immune system, LCK, lymphocyte, self-reactivity, signaling, T cell, TCR, thymus",
author = "Veronika Horkova and Ales Drobek and Daniel Mueller and Celine Gubser and Veronika Niederlova and Lena Wyss and King, {Carolyn G.} and Dietmar Zehn and Ondrej Stepanek",
note = "Funding Information: We thank Ladislav Cupak, Barbara Hausmann, and Rosmarie Lang for their technical assistance and genotyping of mice. We thank Light Microscopy and Flow Cytometry at Institute of Molecular Genetics, namely, Zdenek Cimburek and Dr. Matyas Sima for cell sorting and Dr. Ivan Novotny for assistance with microscopy experiments. We thank Dr. Inken Beck and Dr. Petr Kasparek from the Czech Centre of Phenogenomics for generating Lck−/− mice. We thank Prof. Ed Palmer for his multisided support to the project. We thank Prof. Alfred Signer for providing us with CD8.4 mice. We thank Dr. Tomas Brdicka for providing us with hybridoma-produced antibodies (anti-CD4, anti-CD11b). We thank Dr. Peter Draber for comments on the manuscript. This project was supported by the Swiss National Science Foundation (Promys, IZ11Z0_166538), the Czech Science Foundation (GJ19-03435Y), ERC Starting Grant (FunDiT) to O.S. and ERC Starting Grant (ProtecTC) to D.Z. L.W. is supported by SNSF Early Postdoc Mobility Scholarship (P2BSP3_168719). C.G. is supported by Novartis Foundation. The Group of Adaptive Immunity at the Institute of Molecular Genetics in Prague is supported by an EMBO Installation grant, the Institute of Molecular Genetics of the Czech Academy of Sciences (RVO 68378050), and the J.E.Purkyne Fellowship by the Czech Academy of Sciences (to O.S.). V.H. is a student of the Faculty of Science, Charles University, Prague. The animal facility of the IMG is a part of the Czech Centre for Phenogenomics, and the work there was supported, in part, by grants LM2015040, OP RDI CZ.1.05/2.1.00/19.0395, and OP RDI BIOCEV CZ.1.05/1.1.00/02.0109 provided by the Czech Ministry of Education, Youth and Sports and the European Regional Development Fund. Quantitative phase microscopy was performed in the Microscopy Centre - Light Microscopy Core Facility, IMG ASCR, Prague, Czech Republic, supported by grants (Czech-Bioimaging, MEYS LM2015062), “Centre of Model Organisms” OPPK (CZ.2.16/3.1.00/21547), and “Biomodels for health” (LO1419). V.H. and O.S. planned experiments. V.H. A.D. D.M. C.G. L.W. V.N. and O.S. performed and analyzed experiments. C.G.K. and D.Z. contributed with unique biological material. O.S. performed the mathematical calculations. V.H. and O.S. wrote the manuscript. All authors reviewed the manuscript. O.S. conceived the study. The authors declare no competing interests. Funding Information: We thank Ladislav Cupak, Barbara Hausmann, and Rosmarie Lang for their technical assistance and genotyping of mice. We thank Light Microscopy and Flow Cytometry at Institute of Molecular Genetics, namely, Zdenek Cimburek and Dr. Matyas Sima for cell sorting and Dr. Ivan Novotny for assistance with microscopy experiments. We thank Dr. Inken Beck and Dr. Petr Kasparek from the Czech Centre of Phenogenomics for generating Lck −/− mice. We thank Prof. Ed Palmer for his multisided support to the project. We thank Prof. Alfred Signer for providing us with CD8.4 mice. We thank Dr. Tomas Brdicka for providing us with hybridoma-produced antibodies (anti-CD4, anti-CD11b). We thank Dr. Peter Draber for comments on the manuscript. This project was supported by the Swiss National Science Foundation ( Promys , IZ11Z0_166538 ), the Czech Science Foundation ( GJ19-03435Y ), ERC Starting Grant (FunDiT) to O.S., and ERC Starting Grant (ProtecTC) to D.Z. L.W. is supported by SNSF Early Postdoc Mobility Scholarship ( P2BSP3_168719 ). C.G. is supported by Novartis Foundation . The Group of Adaptive Immunity at the Institute of Molecular Genetics in Prague is supported by an EMBO Installation grant , the Institute of Molecular Genetics of the Czech Academy of Sciences ( RVO 68378050 ), and the J.E.Purkyne Fellowship by the Czech Academy of Sciences (to O.S.). V.H. is a student of the Faculty of Science, Charles University, Prague. The animal facility of the IMG is a part of the Czech Centre for Phenogenomics, and the work there was supported, in part, by grants LM2015040 , OP RDI CZ.1.05/2.1.00/19.0395 , and OP RDI BIOCEV CZ.1.05/1.1.00/02.0109 provided by the Czech Ministry of Education, Youth and Sports and the European Regional Development Fund . Quantitative phase microscopy was performed in the Microscopy Centre - Light Microscopy Core Facility, IMG ASCR, Prague, Czech Republic, supported by grants ( Czech-Bioimaging , MEYS LM2015062 ), “Centre of Model Organisms” OPPK ( CZ.2.16/3.1.00/21547 ), and “Biomodels for health” ( LO1419 ). Publisher Copyright: {\textcopyright} 2020 The Author(s)",
year = "2020",
month = feb,
day = "4",
doi = "10.1016/j.celrep.2020.01.008",
language = "English",
volume = "30",
pages = "1504--1514.e7",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "5",
}