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Germinal Center Formation Motif Signaling in B Cells and Reduced Altered Regulation of FcγRII on Aged Follicular Dendritic Cells Correlates with Immunoreceptor Tyrosine-Based Inhibition Motif Signaling in B Cells and Reduced This information is current as Germinal Center Formation of October 3, 2021. Yüksel Aydar, Péter Balogh, John G. Tew and Andras K. Szakal J Immunol 2003; 171:5975-5987; ; doi: 10.4049/jimmunol.171.11.5975 Downloaded from http://www.jimmunol.org/content/171/11/5975 References This article cites 47 articles, 17 of which you can access for free at: http://www.jimmunol.org/content/171/11/5975.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on October 3, 2021 • Fast Publication! 4 weeks from acceptance to publication *average 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 © 2003 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Altered Regulation of Fc␥RII on Aged Follicular Dendritic Cells Correlates with Immunoreceptor Tyrosine-Based Inhibition Motif Signaling in B Cells and Reduced Germinal Center Formation1 Yu¨ksel Aydar,* Pe´ter Balogh,* John G. Tew,† and Andras K. Szakal2* Aging is associated with reduced trapping of Ag in the form of in immune complexes (ICs) by follicular dendritic cells (FDCs). We postulated that this defect was due to altered regulation of IC trapping receptors. The level of FDC-M1, complement receptors 1 and 2, Fc␥RII, and FDC-M2 on FDCs was immunohistochemically quantitated in draining lymph nodes of actively immunized mice for 10 days after Ag challenge. Initially, FDC Fc␥RII levels were similar but by day 3 a drastic reduction in FDC-Fc␥RII expression was apparent in old mice. FDC-M2 labeling, reflecting IC trapping, was also reduced and correlated with a dramatic Downloaded from reduction in germinal center (GC) B cells as indicated by reduced GC size and number. Nevertheless, labeling of FDC reticula with FDC-M1 and anti-complement receptors 1 and 2 was preserved, indicating that FDCs were present. FDCs in active GCs normally express high levels of FcRs that are thought to bind Fc portions of Abs in ICs and minimize their binding to FcRs on B cells. Thus, cross-linking of B cell receptor and FcR via IC is minimized, thereby reducing signaling via the immunoreceptor tyrosine-based inhibition motif. Old FDCs taken at day 3, when they lack Fc␥RII, were incapable of preventing immunoreceptor tyrosine-based http://www.jimmunol.org/ inhibition motif signaling in wild-type B cells but old FDCs stimulated B cells from Fc␥RIIB؊/؊ mice to produce near normal levels of specific Ab. The present data support the concept that FcR are regulated abnormally on old FDCs. This abnormality correlates with a reduced IC retention and with a reduced capacity of FDCs to present ICs in a way that will activate GC B cells. The Journal of Immunology, 2003, 171: 5975–5987. he follicular dendritic cells (FDCs)3 reside in the light a reduced number of germinal center (GC) B cells (19). Although zone of secondary lymphoid follicles, where their den- there is a marked age-related depression in GC development and T dritic processes interdigitate and form a three-dimen- specific Ab production, the ratio of the FDC reticulum to GC num- sional network, an FDC reticulum (1-4). FDCs function in capture bers remains 1:1 (18–21), emphasizing the dependence of GC de- by guest on October 3, 2021 and long-term retention of immune complexes (ICs) (5–7), the velopment on FDCs even in aging. blocking of apoptosis, the survival of specific B cells (8, 9), and the Fc␥RII and CR2 (CD21) exist on both FDCs and B cells and are promotion of the development of potent high-affinity (10) recall involved in important ligand-receptor interactions including FDC- responses (11, 12). The capture and retention of ICs are mediated Fc␥R-Fc in IC and FDC-CD21 ligand (CD21L)-B cell CD21. by an array of cell surface receptors that include Fc␥RII (13, 14) FDC-CD21L provides B cells with a critical costimulatory signal and complement receptors (complement receptors 1 and 2 (CR1/ and FDC-Fc␥RII minimizes coligation of B cell receptor (BCR) 2)) (15–17). and B cell-FcR (11, 13–17, 22). Fc␥RII is highly expressed on Senescence leads to a pronounced reduction in the secondary FDCs in secondary follicle GCs and the expression pattern of humoral immune response, the appearance of atrophic FDCs (18) Fc␥RII on FDC reticula supports the development of a potent Ab that trap and retain little ICs, produces few iccosomes, and induces response (11, 13, 23). The expression of Fc␥RII on FDCs in GCs is critical for FDCs to retain and mediate the conversion of ICs to a highly immunogenic form and for the generation of strong recall responses (11, 13). Moreover, Fc␥RII promotes the maturation of *Department of Anatomy and Neurobiology, The Immunology Group, and †Depart- the FDC reticulum (24); Fc␥RIIBϪ/Ϫ mice show a substantial de- ment of Microbiology and Immunology, Virginia Commonwealth University, Med- ical College of Virginia, Richmond, VA 23298 lay in the development of FDC reticula (24). The ability of FDCs ␥ Ϫ/Ϫ Received for publication October 24, 2002. Accepted for publication September from Fc RIIB mice to augment Ag-specific IgG production by 22, 2003. wild-type B cells (11, 13) or when incubated with the anti-Fc␥RII The costs of publication of this article were defrayed in part by the payment of page mAb 2.4G2 is markedly depressed. Furthermore, it appears that charges. This article must therefore be hereby marked advertisement in accordance engagement of Ig-Fc with numerous Fc␥RII on FDCs decreases with 18 U.S.C. Section 1734 solely to indicate this fact. the chances of signaling B cells via the immunoreceptor tyrosine- 1 This work was supported by National Institutes of Health Grant AG-17063. Y.A. is the recipient of a scholarship from the Ministry of National Education in Turkey. based inhibition motif (ITIM) induced by cross-linking BCR and B cell Fc␥RII via Ab-Ag complexes (J.G.T., unpublished data). 2 Address correspondence and reprint requests to Dr. Andras K. Szakal, Department of Anatomy and Neurobiology, MCV/VCU, 1101 East Marshall Street, Richmond, Thus, FDCs minimize a negative signal to B cells. VA 23298. E-mail address: [email protected] Although the phenomenon of age-associated reduction in IC 3 Abbreviations used in this paper: FDC, follicular dendritic cell; IC, immune com- trapping in old mice is well known (18, 19), the cellular and mo- plex; GC, germinal center; CD21L, CD21 ligand; CR1/2, complement receptors 1 and 2; ITIM, immunoreceptor tyrosine-based inhibition motif; PNA, peanut agglutinin; lecular bases for this defect have not been defined. Numerous stud- SHIP, Src homology 2-containing inositol phosphatase. ies indicate the importance of Fc␥RII and CR1/2 in IC trapping Copyright © 2003 by The American Association of Immunologists, Inc. 0022-1767/03/$02.00 5976 AGE-RELATED CHANGES IN MOLECULAR INTERACTIONS OF FDC AND B CELLS and mediation of costimulatory signals to B cells in humans as Materials and Methods well as mice (3, 7, 9, 11, 13). However, potential age-related Animals changes in the function and molecular interactions of the Fc␥RII BALB/c mice at 2–3 and 20–21 mo of age were purchased from the Na- and CR1/2 have not been determined. tional Institute on Aging Contract Facility (Harlan, Indianapolis, IN) and Age-related changes in IC trapping, reductions in the FDC re- maintained under specific pathogen-free conditions. The mice were housed ticulum, GC numbers, and size prompted the hypothesis that in old in standard plastic shoebox cages with filter tops. Food and water were mice reduced IC retention is due to a defect in expression of sur- supplied ad libitum. The young mice were used between 2 and 3 mo of age and old mice were used between 21 and 22 mo of age. The mice were face receptors that involve IC trapping. To test this hypothesis, handled in accordance with Virginia Commonwealth University Animal lymph node sections of actively immunized mice were immuno- Care and Use guidelines. histochemically quantitated for Fc␥RII and CR1/2 receptors, for Immunizations FDC reticulum size (anti-FDC-M1), for the capacity to trap ICs (anti-FDC-M2), and for GCs (peanut agglutinin (PNA)). The re- As described previously for active immunization (25, 26), mice received an sults showed that aging reduced the expression of Fc␥RII on FDCs initial 0.1-ml injection s.c. behind the nape of the neck consisting of 200 ␮g/ml aluminum potassium sulfate (A7167; Sigma-Aldrich, St. Louis, by day 3 after Ag challenge that correlated with the reduced trap- MO), precipitated OVA (A5503; Sigma-Aldrich), and 5 ϫ 108 heat-killed ping of ICs (FDC-M2 reactivity). In accordance with these results, Bordetella pertussis. Two weeks later, the mice were given a booster im- old FDCs taken at day 3 could not prevent ITIM signaling and Src munization of 50 ␮g of OVA i.p.
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