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Chain Maturation and Surface Expression Heavy Μ and D Μ Conventional and Surrogate Light Chains Differentially Regulate Ig µ and Dµ Heavy Chain Maturation and Surface Expression This information is current as Terry Fang, Brendan P. Smith and Christopher A. J. Roman of October 5, 2021. J Immunol 2001; 167:3846-3857; ; doi: 10.4049/jimmunol.167.7.3846 http://www.jimmunol.org/content/167/7/3846 Downloaded from References This article cites 73 articles, 34 of which you can access for free at: http://www.jimmunol.org/content/167/7/3846.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on October 5, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts 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 © 2001 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Conventional and Surrogate Light Chains Differentially Regulate Ig ␮ and D␮ Heavy Chain Maturation and Surface Expression1 Terry Fang, Brendan P. Smith, and Christopher A. J. Roman2 Positive selection of precursor (pre-) B cells by Ig membrane ␮ H chains (␮m HC) and counterselection mediated by the truncated HC D␮ depend on the ability of each HC to form a pre-B cell receptor (pre-BCR) signaling complex with the surrogate L chain (SLC) components ␭5 and Vpre-B. To better understand how pre-BCR signaling output is determined by its Ig components and the SLC, we investigated the regulation of pre-BCR surface expression and HC secretory maturation in a new nonlymphoid system. We took this approach as a means to distinguish B-lineage-specific effects from pre-BCR-intrinsic properties that may influence these aspects of pre-BCR homeostasis necessary for signaling. As in pre-B cells, the SLC in nonlymphoid cells supported only a limited degree of ␮m HC maturation and low pre-BCR surface expression levels compared with conventional LCs, Downloaded from indicating that this was due to an intrinsic property of the SLC. We identified the non-Ig region of ␭5 as harboring the restrictive activity responsible for this phenotype. This property of ␭5 was also evident with D␮, but the overall SLC- and L chain-dependent requirements for D␮ maturation and surface expression were markedly different from those for ␮m. Surprisingly, D␮ was modified in an unusual manner that was only dependent on Vpre-B. These results establish a novel function of ␭5 in limiting surface pre-BCR levels and reveal biochemical properties of Ig molecules that may underlie the diverse consequences of pre-BCR signaling in vivo by different HCs. The Journal of Immunology, 2001, 167: 3846–3857. http://www.jimmunol.org/ he expression of (Ig) H and L chains (HC3 and LC) as with ␮m will the new signaling complex formed (the BCR) be able components of signaling complexes on the B cell surface to direct further maturation. Failure to produce a pre-BCR due to T is required to direct early B cell development through a lack of ␭5, the inability to produce a ␮m HC, or deficiencies in discreet stages of differentiation, serving as a quality control mech- Ig␣␤ lead to a developmental block at the progenitor-B cell stage anism to monitor the success of the rearrangement process at each and thus immunodeficiency in humans and mice (3–5). In this way step (reviewed in Ref. 1). For most B cells, the ␮ HC is rearranged developmental progression in vivo is absolutely dependent upon first, and the membrane isoform (␮m) must associate with the in- the productive rearrangement of HC and LC genes and their as- by guest on October 5, 2021 variant surrogate LC (SLC) components ␭5 and Vpre-B to form a sociation into signaling-competent complexes. complex known as the precursor (pre)-B cell receptor (pre-BCR). Despite its critical importance, the molecular mechanisms that The pre-BCR signal directs proliferation and the reprogramming underlie SLC function in pre-BCR signaling are not fully under- of gene expression patterns that allow progenitor-B cells to differ- stood. Sequence homology to conventional LCs, and biochemical entiate into pre-B cells. Also required in the pre-BCR are the in- and genetic evidence support a minimal model for SLC function in ␣ ␤ ␭ tegral membrane proteins Ig and Ig , the cytoplasmic domains of which Vpre-B (a VL-like protein) and 5(aJCL-like protein) form which link the Ig components to signal transduction pathways (2). a LC-like complex that is required to release HCs from the endo- Although necessary for the pre-B transition, the SLC does not plasmic reticulum (ER) by displacing the ER-resident folding guide B cell differentiation beyond the pre-B cell stage; SLC ex- chaperone BiP (Ig binding protein) (6–8) from CH1 and to escort pression is down-regulated, and conventional LC rearrangement is HCs to the cell surface in conjunction with Ig␣␤ (9, 10), where the stimulated. Only if an LC protein is produced that can associate assembled pre-BCR can engage signal transduction pathways (11). Maturation of ␮m proteins is a consequence of their transport Department of Microbiology and Immunology and Morse Institute for Molecular through the secretory pathway, which leads to the modification of Genetics, State University of New York-Downstate Medical Center, Brooklyn, NY N-linked polysaccharides on ␮m from high mannose ER forms to 11203 complex Golgi-dependent forms (12, 13). In support of this model, Received for publication March 19, 2001. Accepted for publication July 30, 2001. ␭5 and Vpre-B associate in the absence of HCs (14–17), and low The costs of publication of this article were defrayed in part by the payment of page amounts of surface ␮m-SLC complexes and trans-Golgi-modified, charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. mature HCs can be detected in normal and transformed pre-B cells 1 This work was supported in part by grants from the American Cancer Society and (18–31). Finally, only HCs that can associate with both SLC com- the New York City Council Speaker’s Fund (to C.A.J.R.) and the New York Academy ponents contribute to the adult pre-B cell pool (32–34). Based on of Medicine (to B.P.S.). this activity, a quantitative model for SLC function in pre-BCR- 2 Address correspondence and reprint requests to Dr. Christopher A. J. Roman, De- dependent positive selection has been proposed in which the lim- partment of Microbiology and Immunology and Morse Institute for Molecular Ge- netics, 450 Clarkson Avenue, Box 44, State University of New York-Downstate Med- iting parameter for proliferative expansion of a pre-B cell clone is ical Center, Brooklyn, NY 11203. E-mail address: [email protected] the number of pre-BCRs on its surface, proportional to the ability 3 Abbreviations used in this paper: HC, H chain; BCR, B cell receptor; Endo H, of the HC to associate with the SLC (35). endoglycosidase H; ER, endoplasmic reticulum; GFP, green fluorescent protein; However, unlike LCs, ␭5 and Vpre-B are products of separate, HEK, human embryonic kidney; LC, L chain; ␮m, membrane ␮; pre-, precursor; PNGase F, peptide:N-glycosidase F; PSA, Pisum savatum agglutinin; RCA, Ricin nonpolymorphic, nonrearranging genes and contain non-Ig-like re- communis agglutinin; SLC, surrogate LC; (S)LC, surrogate and conventional LC. gions (36–39) that may have a specialized function. Interestingly, Copyright © 2001 by The American Association of Immunologists 0022-1767/01/$02.00 The Journal of Immunology 3847 part of the non-Ig region of human ␭5/14.1 has the unusual prop- ␭1 (aa 1–19) to the first amino acid of the respective J region via overlap erty of inhibiting ␭5 folding (40), suggesting that it may also have PCR. The Vpre-B-1 cDNA was amplified from pZ121 (37). Vpre-B⌬C an important role in controlling pre-BCR homeostasis. In contrast was made by overlap PCR to generate a stop codon after amino acid 122 of Vpre-B-1. to the BCR, surface pre-BCR levels are very low, but it has not Other expression constructs. Ig␣ and Ig␤ cDNAs were amplified by PCR been fully resolved whether this is a pre-BCR-intrinsic property or from the plasmids pCL2-T3 (56) and pTZ18-1A94 (57), respectively, using a B-lineage-specific effect. Given the low amounts of surface pre- oligonucleotide primers that restored to each their normal translation ini- BCRs, it is also possible that the SLC may not only have a quan- tiation sequence. pEBB-green fluorescent protein (GFP) was created by titative role by allowing surface pre-BCR transport, but may also subcloning the GFP insert from MSCV-hGFP (gift from Dr. J. Jacob, Emory University, Atlanta, GA) into pEBB. have a qualitative role in activating surface pre-BCR signaling (41). Although the molecular nature of the triggering mechanism is Cell culture and transient transfections not fully understood, the developmental pre-BCR signal may be Human embryonic kidney (HEK) epithelial 293 cells were maintained in the result of an inherent constitutive activity, i.e., that it does not DMEM supplemented with 10% heat-inactivated FCS, 50 U/ml penicillin, require cross-linking by a putative pre-BCR-ligand (2, 11, 42–45).
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