Antigen Receptor Allelic Exclusion: An Update and Reappraisal Brenna L. Brady, Natalie C. Steinel and Craig H. Bassing This information is current as J Immunol 2010; 185:3801-3808; ; of October 2, 2021. doi: 10.4049/jimmunol.1001158 http://www.jimmunol.org/content/185/7/3801 References This article cites 66 articles, 32 of which you can access for free at: Downloaded from http://www.jimmunol.org/content/185/7/3801.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 Subscription Information about subscribing to The Journal of Immunology is online at: by guest on October 2, 2021 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 © 2010 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Antigen Receptor Allelic Exclusion: An Update and Reappraisal Brenna L. Brady,1 Natalie C. Steinel,1 and Craig H. Bassing Most lymphocytes express cell surface Ag receptor Monoallelic gene expression is a general phenomenon critical chains from single alleles of distinct Ig or TCR loci. for normal biology. This regulation is pervasive during genetic Since the identification of Ag receptor allelic exclusion, imprinting and X chromosome inactivation, enforcing gene the importance of this process and the precise molec- silencing in all cell types (3). Defects in X chromosome in- ular mechanisms by which it is achieved have remained activation and imprinting were found to cause human dis- enigmatic. This brief review summarizes current knowl- orders, which defined the relevance of these processes and edge of the extent to which Ig and TCR loci are subject facilitated their investigation by studying clear phenotypes. In contrast, defects in olfactory or Ag receptor allelic exclusion, to allelic exclusion. Recent progress in studying and de- Downloaded from fining mechanistic steps and molecules that may control which silence tissue-specific genes in distinct lineages, have the monoallelic initiation and subsequent inhibition of not been linked unequivocally to any symptoms in humans V-to-(D)-J recombination is outlined using the mouse (3). However, dysfunction of these tissue-specific processes may result in subtle phenotypes or may be compensated by TCRb locus as a model with frequent comparisons to additional mechanisms, either of which would mask their k the mouse IgH and Ig loci. Potential consequences of significance and provide obstacles for investigation. defects in mechanisms that control Ag receptor allelic http://www.jimmunol.org/ exclusion and a reappraisal of the physiologic relevance Allelic exclusion, self tolerance, and autoimmunity of this immunologic process also are discussed. The A long-standing tenent of adaptive immunity is that virtually Journal of Immunology, 2010, 185: 3801–3808. all lymphocytes express surface TCR or Ig chains from one allele to ensure monospecific Ag recognition and suppress autoim- munity by facilitating central tolerance to self-reactive lympho- ntigen receptor allelic exclusion is defined as the cytes. However, this notion is not supported by current know- surface expression of Ig or TCR chains from a single ledge. Flow cytometry reveals IgH allelic inclusion in only A allelic copy of corresponding genetic loci. Pernis et al. 0.01% of mouse B cells (4), but allelic inclusion of Igk and by guest on October 2, 2021 (1) identified this phenomenon in the 1960s while studying Ig TCR loci in at least 1–10% of mouse lymphocytes (Table I) expression on rabbit lymphocytes, providing evidence for the (5–9). Thus, a significant fraction of normal mouse (and where “one lymphocyte–one antigen receptor” concept of Burnett’s assayed human) lymphocytes express surface Igk or TCR clonal selection theory. Analyses of Ig rearrangements in the chains from both alleles, refuting the “one lymphocyte–one early 1980s suggested that the assembly and expression of an antigen receptor” concept. In addition, recognition of multiple Ag receptor chain from one allele inhibit further V-to-(D)-J distinct ligands is known now to be a general and inherent recombination on the other allele (2). Evidence for such feed- property of T and B cell Ag receptors (10), meaning that far back regulation was provided over the next decade by dem- more than the 1–10% of allelically included lymphocytes onstrations that preassembled Ig or TCR transgenes enforce exhibits poly-specific Ag recognition. Because primary TCR allelic exclusion through inhibiting V-to-(D)-J rearrange- and BCR repertoires include receptors capable of bind- ments (2). These observations helped establish the current ing self-Ags, organisms with adaptive immune systems must dogma that allelic exclusion is maintained by feedback regu- possess central ability to tolerate the generation of autoreactive lation to ensure virtually every lymphocyte exhibits monospe- lymphocytes and thereby prevent autoimmunity. Central tol- cific Ag recognition. erance mechanisms include deletion, stalled maturation, an- Although Ag receptor allelic exclusion has been investigated ergy, or receptor editing (9). In the 1990s, analyses of TCR for almost 50 y, the importance of this process and the precise and Ig transgenic mice demonstrated that dual expression of mechanisms by which it is achieved remain largely unknown. self-reactive and non–self-reactive receptors enables developing Immunology Graduate Group, Division of Cancer Pathobiology, Department of Pa- School of Medicine; and National Institutes of Health Grant R01 CA125195 (to thology and Laboratory Medicine, Center for Childhood Cancer Research, Children’s C.H.B.). Hospital of Philadelphia, University of Pennsylvania School of Medicine, Abramson Address correspondence and reprint requests to Dr. Craig H. Bassing, Children’s Hos- Family Cancer Research Institute, Philadelphia, PA 19104 pital of Philadelphia, 4054 Colket Translational Research Building, 3501 Civic Center 1B.L.B. and N.C.S. contributed equally to this review. Boulevard, Philadelphia, PA 19104. E-mail address: [email protected] Received for publication June 23, 2010. Accepted for publication August 5, 2010. Abbreviations used in this paper: ATM, ataxia telangiectasia mutated; DN, double negative; DP, double positive; Eb, TCRb enhancer; pDb1, Db1 promoter. This work was supported by Training Grant TG GM-07229 of the University of Pennsylvania (to B.L.B.); the Department of Pathology and Laboratory Medicine and Ó the Center for Childhood Cancer Research of the Children’s Hospital of Philadelphia; Copyright 2010 by The American Association of Immunologists, Inc. 0022-1767/10/$16.00 the Abramson Family Cancer Research Institute of the University of Pennsylvania www.jimmunol.org/cgi/doi/10.4049/jimmunol.1001158 3802 BRIEF REVIEWS: Ag RECEPTOR ALLELIC EXCLUSION Table I. Allelic inclusion of mouse Ag receptor loci Biallelic In-Frame Locus Allelic Inclusion (%) Experimental Approach V(D)J (%) References IgH 0.01 Natural allotypic differences 2–5 4, 18 Igk 1–7 Hemizygous human Ck knock-in 11 5, 6 TCRa 10 Anti-Va combinations 30 9, 19 TCRb 1–3 Anti-Vb combinations 2–10 8, 20, 22 TCRd 3 Anti-Vd combinations 35 7, 21 TCRg 1 Anti-Vg combinations 10 7 T and B cells to escape deletion and differentiate into mature TCRa allelic inclusion to ∼10% (Table I) (9, 19). Similar lymphocytes that possess autoreactive potential in vitro, yet sequence analyses of Igk, TCRb,TCRg, and TCRd rearrange- generally fail to cause autoimmunity in vivo (11–13). These ments revealed two in-frame genes in 2–35% of cells depend- additional tolerance mechanisms restrain the systemic activa- ing upon the locus (Table I) (5, 7, 20–22). These percentages tion of lymphocytes expressing both self-reactive and non–self- are higher than the corresponding allelic inclusion frequencies, reactive receptors. A separate line of investigation demon- suggesting that pairing restrictions or other mechanisms con- strated that the destructive potential of autoreactive lympho- tribute to Igk,TCRb, TCRg, and TCRd allelic exclusion. cytes that escape central tolerance is restrained through Consistent with this notion, silencing of in-frame V-D-J-Cb Downloaded from dominant peripheral tolerance mechanisms, such as those con- genes at the transcriptional and posttranscriptional levels con- trolled by regulatory T and B cells (14, 15). In this context, tributes to TCRb allelic exclusion mouse ab T cells (20, 23). allelic exclusion might function as an early cell-autonomous These data indicate that multiple mechanisms function in a suc- tolerance mechanism to reduce the frequency of developing cessive manner to limit the frequency of cells with surface lymphocytes with expression of two or more poly-specific Ag expression of Ig or TCR chains from both allelic copies of receptors and thereby facilitate central tolerance. If defects in corresponding loci. In this context, defects in mechanisms that http://www.jimmunol.org/ allelic exclusion overwhelmed central tolerance mechanisms, control feedback inhibition