The Influence of MHC Class II on B Cell Defects Induced by Invariant Chain/CD74 N-Terminal Fragments
Schneppenheim J, Loock AC, Huettl S, Schweizer M, Luellmann-Rauch R, Oberg HH, Arnold P, Lehmann C, Dudziak D, Kabelitz D, Lucius R, Lennon-Dumenil AM, Saftig P, Schroeder B (2017)
Publication Type: Journal article
Publication year: 2017
Journal
Book Volume: 199
Pages Range: 172-185
Journal Issue: 1
Abstract
The invariant chain (CD74) mediates assembly and targeting of MHC class II (MHCII) complexes. In endosomes, CD74 undergoes sequential degradation by different proteases, including cathepsin S (CatS) and the intramembrane protease signal peptide peptidase-like 2a (SPPL2a). In their absence, CD74 N-terminal fragments (NTFs) accumulate. In SPPL2a-/- B cells, such an NTF impairs endosomal trafficking and BCR signal transduction. In mice, this leads to a loss of splenic B cells beyond the transitional stage 1. To gain insight into CD74 determinants and the role of MHCII, we compared B cells from CatS-/- , SPPL2a-/- , and SPPL2a-MHCII double-deficient mice. We assessed differentiation of B cells in bone marrow and spleen and analyzed their endosomal morphology, BCR expression, and signal transduction. We demonstrate that MHCII is dispensable for the B cell phenotype of SPPL2a-/- mice, further supporting a CD74-intrinsic effect. Despite significant vacuolization of endosomal compartments similar to SPPL2a-/- B cells, CatS-/- traditional stage 1 B cells show unimpaired degradation of endocytic cargo, have intact BCR signaling, and do not exhibit any relevant defects in maturation. This could indicate that CD74 NTF-induced structural changes of endosomes are not directly involved in these processes. We further found that the block of CD74 degradation in CatS-/- B cells is incomplete, so that NTF levels are significantly lower than in SPPL2a-/- B cells. This suggests a dose dependency and threshold for the CD74 NTF-associated impairment of B cell signaling and maturation. In addition, different functional properties of the longer, MHCII-bound CD74 NTF could contribute to the milder phenotype of CatS-/- B cells.
Authors with CRIS profile
Philipp Arnold
Christian Lehmann Department of Dermatology Diana Dudziak Professur für die Biologie Dendritischer Zellen
Christian Lehmann Department of Dermatology Diana Dudziak Professur für die Biologie Dendritischer Zellen
Additional Organisation(s)
Involved external institutions
Christian-Albrechts-Universität zu Kiel
Germany (DE)
Universitätsklinikum Hamburg-Eppendorf (UKE)
Germany (DE)
PSL Research University / Université de recherche Paris Sciences et Lettres
France (FR)
Germany (DE)
Universitätsklinikum Hamburg-Eppendorf (UKE)
Germany (DE)
PSL Research University / Université de recherche Paris Sciences et Lettres
France (FR)
How to cite
APA:
Schneppenheim, J., Loock, A.-C., Huettl, S., Schweizer, M., Luellmann-Rauch, R., Oberg, H.-H.,... Schroeder, B. (2017). The Influence of MHC Class II on B Cell Defects Induced by Invariant Chain/CD74 N-Terminal Fragments. Journal of Immunology, 199(1), 172-185. https://doi.org/10.4049/jimmunol.1601533
MLA:
Schneppenheim, Janna, et al. "The Influence of MHC Class II on B Cell Defects Induced by Invariant Chain/CD74 N-Terminal Fragments." Journal of Immunology 199.1 (2017): 172-185.
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