Ligand Binding of CD22 and Siglec-G Determines Distinct Functions but Is Dispensable for B Cell Tolerance Induction This information is current as of September 29, 2021. Lamia Özgör, Sarah J. Meyer, Marina Korn, Klara Terörde and Lars Nitschke J Immunol published online 24 August 2018 http://www.jimmunol.org/content/early/2018/08/23/jimmun ol.1800296 Downloaded from

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The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2018 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published August 24, 2018, doi:10.4049/jimmunol.1800296 The Journal of Immunology

Sialic Acid Ligand Binding of CD22 and Siglec-G Determines Distinct B Cell Functions but Is Dispensable for B Cell Tolerance Induction

Lamia O¨ zgo¨r, Sarah J. Meyer,1 Marina Korn,1 Klara Tero¨rde, and Lars Nitschke

Siglec-G and CD22 are inhibitory receptors on B cells and play an important role in the maintenance of tolerance. Although both molecules are expressed on all B cell populations at a similar level, Siglec-G was found to regulate exclusively B1a cells, whereas CD22 functions as an inhibitory receptor specifically on B2 cells. It is known that the mechanistic function of both Siglecs is regulated by sialic acid binding in a reciprocal manner, although it was not known until now how B cells would act when both Siglec-G and CD22 lack their ability to bind sialic acids. We answered this question by analyzing Siglec-G R120E x CD22 R130E mice. These mice show decreased numbers of mature recirculating B cells in the bone marrow similar to mice with mutations in CD22. Also, Downloaded from they show an increased B1a cell population in peritoneal cavity and a skewed BCR repertoire in peritoneal B1a cells, which is characteristic for mice with mutated Siglec-G. Ca2+ mobilization was strongly reduced in B2 cells and was altered in peritoneal B1a cells, whereas B cell survival was neither affected in B2 cells nor in B1a cells. Also, aging Siglec-G R120E x CD22 R130E mice do neither develop a general hyperactivated immune status nor autoimmunity. This demonstrates that Siglec binding to sialic acids as abundant self-ligands cannot be a dominant mechanism for the Siglec-mediated B cell tolerance induction. The Journal of Immunology, 2018, 201: 000–000. http://www.jimmunol.org/

any mechanisms exist in our immune system to keep signaling, their exact function often remains elusive (4, 5). The the balance between inducing a rapid and effective Siglec family is divided in highly conserved Siglecs, called so be- M immune response against pathogens and the mainte- cause they are highly conserved between mammalians and CD33- nance of tolerance. One family, which is supposed to act related Siglecs. Those CD33-related Siglecs share high sequence as an immune fine tuner for these processes, is the sialic acid– homology to CD33 but underwent very rapid evolution (6). binding Ig-like