Abstract
MHC class I (MHC I) expression in the host influences NK cells in a process termed education. The result of this education is reflected in the responsiveness of NK cells at the level of individual cells as well as in the repertoire of inhibitory MHC I‒specific receptors at the NK cell system level. The presence of MHC I molecules in the host environment gives rise to a skewed receptor repertoire in spleen NK cells where subsets expressing few (one or two) inhibitory receptors are expanded whereas subsets with many (three or more) receptors are contracted. It is not known whether this MHC I‒dependent skewing is imposed during development or after maturation of NK cells. In this study, we tested the hypothesis that the NK cell receptor repertoire is shaped already early during NK cell development in the bone marrow. We used mice with a repertoire imposed by a single MHC I allele, as well as a C57BL/6 mutant strain with exaggerated repertoire skewing, to investigate Ly49 receptor repertoires at different stages of NK cell differentiation. Our results show that NK cell inhibitory receptor repertoire skewing can indeed be observed in the bone marrow, even during the earliest developmental steps where Ly49 receptors are expressed. This may partly be accounted for by selective proliferation of certain NK cell subsets, but other mechanisms must also be involved. We propose a model for how repertoire skewing is established during a developmental phase in the bone marrow, based on sequential receptor expression as well as selective proliferation.
Original language | English |
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Pages (from-to) | 751-759 |
Number of pages | 9 |
Journal | Journal of Immunology |
Volume | 209 |
Issue number | 4 |
DOIs | |
State | Published - 15 Aug 2022 |
Bibliographical note
Publisher Copyright:Copyright © 2022 by The American Association of Immunologists, Inc.
Funding
This work was supported by grants from the Karolinska Institutet, the Swedish Foundation for Strategic Research, Swedish Research Council Grant 2016-02737, and the Swedish Cancer Society (all to K.K.). This work was also supported by the Karolinska Institutet, the Åke Wiberg Foundation, the Magnus Bergwall Foundation, the Royal Swedish Academy of Sciences, the Syskonen Svensson Foundation, and the Swedish National Board of Health and Welfare (all to M.H.J.); Swedish Society for Medical Research Grant S17-0104, Swedish Cancer Foundation Grant 19 0408 Fk, Swedish Medical Association Grant SLS-59451, Stockholm County Council Grants (RS2020-0731 and Clinical Research Appointment 20190859), Edvard Welander Foundation Grant 3147, Clas Groschinsky Memorial Foundation Grant M19390, Åke Wiberg Foundation Grant M19-0665, Magnus Bergvall Foundation Grant 2019-03538, and Karolinska Institutet Foundation Grant 2018-02203 (all to H.B.); KID grants from the Karolinska Institutet (to A.K.W. and S.L.W.) and the Wenner-Gren Foundations (to M.E.). This work was supported by grants from the Karolinska Institutet, the Swedish Foundation for Strategic Research, Swedish Research Council Grant 2016-02737, and the Swedish Cancer Society (all to K.K.). This work was also supported by the Karolinska Institutet, the Åke Wiberg Foundation, the Magnus Bergwall Foundation, the Royal Swedish Academy of Sciences, the Syskonen Svensson Foundation, and the Swedish National Board of Health and Welfare (all to M.H.J.); Swedish Society for Medical Research Grant S17-0104, Swedish Cancer Foundation Grant 19 0408 Fk, Swedish Medical Association Grant SLS-59451, Stockholm County Council Grants (RS2020-0731 and Clinical Research Appointment 20190859), Edvard Welander Foundation Grant 3147, Clas Groschinsky Memorial Foundation Grant M19390, Åke Wiberg Foundation Grant M19-0665, Magnus Bergvall Foundation Grant 2019-03538, and Karolinska Institutet Foundation Grant 2018-02203 (all to H.B.); KID grants from the Karolinska Institutet (to A.K.W. and S.L.W.) and the Wenner-Gren Foundations (to M.E.). We are grateful to Margareta Hagelin, Maj-Britt Alter, Kenth Andersson, and Anna-Karin Person for expert assistance with in vivo experiments. All members of Petter Höglund’s, Björn Önfelt’s, Benedict Chambers’ and Klas Kärre’s groups are acknowledged for stimulating discussions. The visual abstract and Fig. 6 were created with BioRender.com.
Funders | Funder number |
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Karolinska Institutet Foundation | 2018-02203 |
Margareta Hagelin | |
Syskonen Svensson Foundation | |
Åke Wiberg Stiftelse | |
Swedish Cancer Foundation | 19 0408 Fk |
Wenner-Gren Stiftelserna | |
Royal Swedish Academy of Sciences | |
Stiftelsen för Strategisk Forskning | |
Cancerfonden | |
Svenska Sällskapet för Medicinsk Forskning | S17-0104 |
Karolinska Institutet | |
Stockholms Läns Landsting | RS2020-0731, 20190859 |
Vetenskapsrådet | 2016-02737 |
Socialstyrelsen | |
Magnus Bergvalls Stiftelse | 2019-03538 |
Stiftelsen Clas Groschinskys Minnesfond | M19390, M19-0665 |
Sveriges Läkarförbund | SLS-59451 |
Edvard Welanders Stiftelse | 3147 |