MHC Class I‒Dependent Shaping of the NK Cell Ly49 Receptor Repertoire Takes Place Early during Maturation in the Bone Marrow

Stina L. Wickström, Arnika K. Wagner, Sina Fuchs, Marjet Elemans, Joanna Kritikou, Ramit Mehr, Klas Kärre, Maria H. Johansson, Hanna Brauner

Research output: Contribution to journalArticlepeer-review

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 languageEnglish
Pages (from-to)751-759
Number of pages9
JournalJournal of Immunology
Volume209
Issue number4
DOIs
StatePublished - 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.

FundersFunder number
Karolinska Institutet Foundation2018-02203
Margareta Hagelin
Syskonen Svensson Foundation
Åke Wiberg Stiftelse
Swedish Cancer Foundation19 0408 Fk
Wenner-Gren Stiftelserna
Royal Swedish Academy of Sciences
Stiftelsen för Strategisk Forskning
Cancerfonden
Svenska Sällskapet för Medicinsk ForskningS17-0104
Karolinska Institutet
Stockholms Läns LandstingRS2020-0731, 20190859
Vetenskapsrådet2016-02737
Socialstyrelsen
Magnus Bergvalls Stiftelse2019-03538
Stiftelsen Clas Groschinskys MinnesfondM19390, M19-0665
Sveriges LäkarförbundSLS-59451
Edvard Welanders Stiftelse3147

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