clonal deletion


Summary: Removal, via CELL DEATH, of immature lymphocytes that interact with antigens during maturation. For T-lymphocytes this occurs in the thymus and ensures that mature T-lymphocytes are self tolerant. B-lymphocytes may also undergo clonal deletion.

Top Publications

  1. Starr T, Jameson S, Hogquist K. Positive and negative selection of T cells. Annu Rev Immunol. 2003;21:139-76 pubmed
    ..We also discuss emerging data on the selection of regulatory T cells. Such cells require a high-affinity interaction with self-antigens, yet differentiate into regulatory cells instead of being eliminated. ..
  2. Grillot D, Merino R, Nunez G. Bcl-XL displays restricted distribution during T cell development and inhibits multiple forms of apoptosis but not clonal deletion in transgenic mice. J Exp Med. 1995;182:1973-83 pubmed
    ..However, Bcl-xL was unable to block clonal deletion of thymocytes reactive with self-superantigens or H-Y antigen...
  3. Thien M, Phan T, Gardam S, Amesbury M, Basten A, Mackay F, et al. Excess BAFF rescues self-reactive B cells from peripheral deletion and allows them to enter forbidden follicular and marginal zone niches. Immunity. 2004;20:785-98 pubmed
    ..This partial subversion of B cell self tolerance is likely to underlie the autoimmunity associated with BAFF overexpression. ..
  4. von Boehmer H, Kisielow P. Negative selection of the T-cell repertoire: where and when does it occur?. Immunol Rev. 2006;209:284-9 pubmed
  5. Simon A, Williams O, Mongkolsapaya J, Jin B, Xu X, Walczak H, et al. Tumor necrosis factor-related apoptosis-inducing ligand in T cell development: sensitivity of human thymocytes. Proc Natl Acad Sci U S A. 2001;98:5158-63 pubmed
    ..Thus, susceptibility to TRAIL-induced apoptosis is controlled differently by central and peripheral T cells...
  6. Page D, Roberts E, Peschon J, Hedrick S. TNF receptor-deficient mice reveal striking differences between several models of thymocyte negative selection. J Immunol. 1998;160:120-33 pubmed
    ..Current models of negative selection and the role of TNFR family members in this process are discussed in light of these results. ..
  7. Su Y, Huang X, Wang S, Min W, Yin Z, Jevnikar A, et al. Double negative Treg cells promote nonmyeloablative bone marrow chimerism by inducing T-cell clonal deletion and suppressing NK cell function. Eur J Immunol. 2012;42:1216-25 pubmed publisher
    ..Taken together, our results suggest that adoptive transfer of DN Treg cells can control both adoptive and innate immunities and promote stable-mixed chimerism and donor-specific tolerance in the irradiation-free regimen. ..
  8. Surh C, Sprent J. T-cell apoptosis detected in situ during positive and negative selection in the thymus. Nature. 1994;372:100-3 pubmed
    ..Negative selection of V beta 5+ cells is thus restricted to the medulla. ..
  9. Piazzon I, Goldman A, Torello S, Nepomnaschy I, Deroche A, Dran G. Transmission of an Mls-1a-like superantigen to BALB/c mice by foster-nursing on F1 Mls-1bxa mothers. Sex-influenced onset of clonal deletion. J Immunol. 1994;153:1553-62 pubmed
    ..1+ T cells in 50% of the litter. The onset of this Mls-1a-like clonal deletion was markedly sex-influenced, being earlier in females (8-10 wk of age) than in males (32 wk)...

More Information


  1. Pobezinsky L, Angelov G, Tai X, Jeurling S, Van Laethem F, Feigenbaum L, et al. Clonal deletion and the fate of autoreactive thymocytes that survive negative selection. Nat Immunol. 2012;13:569-78 pubmed publisher
    b>Clonal deletion of autoreactive thymocytes is important for self-tolerance, but the intrathymic signals that induce clonal deletion have not been clearly identified...
  2. Hubert F, Kinkel S, Davey G, Phipson B, Mueller S, Liston A, et al. Aire regulates the transfer of antigen from mTECs to dendritic cells for induction of thymic tolerance. Blood. 2011;118:2462-72 pubmed publisher
    ..It also indicates that mTECs can mediate tolerance by direct presentation of Aire-regulated antigens to both CD4 and CD8 T cells. ..
  3. Higuchi M, Zeng D, Shizuru J, Gworek J, Dejbakhsh Jones S, Taniguchi M, et al. Immune tolerance to combined organ and bone marrow transplants after fractionated lymphoid irradiation involves regulatory NK T cells and clonal deletion. J Immunol. 2002;169:5564-70 pubmed induced in either IL-4(-/-) or IL-10(-/-) hosts given the regimen despite the development of chimerism and clonal deletion of host T cells to donor MHC-Ags in the IL-10(-/-) hosts...
  4. Hippen K, Schram B, Tze L, Pape K, Jenkins M, Behrens T. In vivo assessment of the relative contributions of deletion, anergy, and editing to B cell self-tolerance. J Immunol. 2005;175:909-16 pubmed
    ..These data identify receptor editing as a major physiologic mechanism by which highly self-reactive B cells are tolerized to membrane and soluble self-Ags. ..
  5. Preda Pais A, Stan A, Casares S, Bona C, Brumeanu T. Efficacy of clonal deletion vs. anergy of self-reactive CD4 T-cells for the prevention and reversal of autoimmune diabetes. J Autoimmun. 2005;25:21-32 pubmed
    ..Herein, we show that an octameric form of DEF has doubled the period of protection and reversal of disease by clonal deletion of diabetogenic CD4 T-cells in both the thymic and peripheral compartments...
  6. Hogquist K, Baldwin T, Jameson S. Central tolerance: learning self-control in the thymus. Nat Rev Immunol. 2005;5:772-82 pubmed
    ..In the thymus, one of the main mechanisms of T-cell central tolerance is clonal deletion, although the selection of regulatory T cells is also important and is gaining enormous interest...
  7. Kawahata K, Misaki Y, Yamauchi M, Tsunekawa S, Setoguchi K, Miyazaki J, et al. Generation of CD4(+)CD25(+) regulatory T cells from autoreactive T cells simultaneously with their negative selection in the thymus and from nonautoreactive T cells by endogenous TCR expression. J Immunol. 2002;168:4399-405 pubmed
    ..10 mice had increased numbers of CD4(+)CD25(+) regulatory T cells in the thymus and the periphery despite clonal deletion. In Ld-nOVA x DO11...
  8. Gao J, Zhang H, Bai X, Wen J, Zheng X, Liu J, et al. Perinatal blockade of b7-1 and b7-2 inhibits clonal deletion of highly pathogenic autoreactive T cells. J Exp Med. 2002;195:959-71 pubmed
    ..vitro studies have suggested that costimulatory molecules B7-1 and B7-2 and their receptor CD28 can promote clonal deletion, and limited in vivo studies have indicated that CD28 is involved in the clonal deletion of some T cells...
  9. Li R, Page D. Requirement for a complex array of costimulators in the negative selection of autoreactive thymocytes in vivo. J Immunol. 2001;166:6050-6 pubmed
    ..We predict that different sets of costimulators will be required depending on the timing of negative selection, the Ag, the signal strength, the APC, and whether Ag presentation occurs on class I or class II MHC molecules. ..
  10. McGargill M, Ch en I, Katayama C, Pages G, Pouyssegur J, Hedrick S. Cutting edge: Extracellular signal-related kinase is not required for negative selection of developing T cells. J Immunol. 2009;183:4838-42 pubmed publisher
    ..Results from three different models reveal that thymocyte deletion remains intact in the absence of Erk. ..
  11. Zhou T, Cheng J, Yang P, Wang Z, Liu C, Su X, et al. Inhibition of Nur77/Nurr1 leads to inefficient clonal deletion of self-reactive T cells. J Exp Med. 1996;183:1879-92 pubmed
    ..To determine the role of this family of DNA-binding proteins in thymic clonal deletion, transgenic (Tg) mice bearing a dominant negative mutation were produced...
  12. Baldwin T, Hogquist K. Transcriptional analysis of clonal deletion in vivo. J Immunol. 2007;179:837-44 pubmed
    ..thymocytes initiates either a program of survival and differentiation (positive selection) or death (clonal deletion), which is dictated in large part by the affinity of the TCR for self-peptide-MHC complexes...
  13. Mackay I. Autoimmunity since the 1957 clonal selection theory: a little acorn to a large oak. Immunol Cell Biol. 2008;86:67-71 pubmed
  14. McCaughtry T, Hogquist K. Central tolerance: what have we learned from mice?. Semin Immunopathol. 2008;30:399-409 pubmed publisher
    ..results from the induction of anergy, receptor editing, clonal diversion (agonist selection), and/or clonal deletion (apoptosis) in self-reactive clones...
  15. Choisy Rossi C, Holl T, Pierce M, Chapman H, Serreze D. Enhanced pathogenicity of diabetogenic T cells escaping a non-MHC gene-controlled near death experience. J Immunol. 2004;173:3791-800 pubmed
  16. Foy T, Page D, Waldschmidt T, Schoneveld A, Laman J, Masters S, et al. An essential role for gp39, the ligand for CD40, in thymic selection. J Exp Med. 1995;182:1377-88 pubmed
    ..Moreover, the data support the hypothesis that, for negative selection to some endogenously produced antigens, negative selection may be dependent on TCR engagement and costimulation. ..
  17. Liston A, Lesage S, Wilson J, Peltonen L, Goodnow C. Aire regulates negative selection of organ-specific T cells. Nat Immunol. 2003;4:350-4 pubmed
    ..These results indicate that autoimmune polyendocrinopathy syndrome 1 is caused by failure of a specialized mechanism for deleting forbidden T cell clones, establishing a central role for this tolerance mechanism. ..
  18. Lamhamedi Cherradi S, Zheng S, Maguschak K, Peschon J, Chen Y. Defective thymocyte apoptosis and accelerated autoimmune diseases in TRAIL-/- mice. Nat Immunol. 2003;4:255-60 pubmed
    ..Thus, TRAIL mediates thymocyte apoptosis and is important in the induction of autoimmune diseases. ..
  19. Bugeon L, Hargreaves R, Crompton T, Outram S, Rahemtulla A, Porter A, et al. Selective silencing of full-length CD80 but not IgV-CD80 leads to impaired clonal deletion of self-reactive T cells and altered regulation of immune responses. Eur J Immunol. 2001;31:118-27 pubmed
    ..CD86, whilst critical to primary T cell activation, made only a minor contribution to re-activation of normal cells. ..
  20. Gallegos A, Bevan M. Central tolerance: good but imperfect. Immunol Rev. 2006;209:290-6 pubmed
    ..In addition, we recently investigated the efficiency of central tolerance to TSA during ontogeny, and we report that this process was less efficient in neonates than adult animals. ..
  21. Merkenschlager M, Graf D, Lovatt M, Bommhardt U, Zamoyska R, Fisher A. How many thymocytes audition for selection?. J Exp Med. 1997;186:1149-58 pubmed
  22. Sohn S, Thompson J, Winoto A. Apoptosis during negative selection of autoreactive thymocytes. Curr Opin Immunol. 2007;19:510-5 pubmed
    ..This and other possibilities will be discussed to explain the unresolved finding that negative selection is defective in Bim(-/-) but is not efficiently blocked in Bcl-2 transgenic mice. ..
  23. Holler P, Yamagata T, Jiang W, Feuerer M, Benoist C, Mathis D. The same genomic region conditions clonal deletion and clonal deviation to the CD8alphaalpha and regulatory T cell lineages in NOD versus C57BL/6 mice. Proc Natl Acad Sci U S A. 2007;104:7187-92 pubmed which immature thymocytes expressing a self-reactive T cell antigen receptor (TCR) are rescued from clonal deletion by adopting an alternative differentiation pathway resistant to apoptosis...
  24. Zheng X, Gao J, Zhang H, Geiger T, Liu Y, Zheng P. Clonal deletion of simian virus 40 large T antigen-specific T cells in the transgenic adenocarcinoma of mouse prostate mice: an important role for clonal deletion in shaping the repertoire of T cells specific for antigens overexpressed in solid tumor. J Immunol. 2002;169:4761-9 pubmed
    ..To examine whether the T cell clonal deletion is responsible for the tolerance, we crossed the TRAMP mice with mice transgenic for a rearranged TCR ..
  25. Zhang M, Vacchio M, Vistica B, Lesage S, Egwuagu C, Yu C, et al. T cell tolerance to a neo-self antigen expressed by thymic epithelial cells: the soluble form is more effective than the membrane-bound form. J Immunol. 2003;170:3954-62 pubmed
  26. Ryu H, Mann K, Schlezinger J, Jensen B, Sherr D. Environmental chemical-induced pro/pre-B cell apoptosis: analysis of c-Myc, p27Kip1, and p21WAF1 reveals a death pathway distinct from clonal deletion. J Immunol. 2003;170:4897-904 pubmed
    ..The PAH-induced death signaling pathway resembles the signaling cascade activated during clonal deletion and modeled by B cell receptor cross-linking or by dexamethasone exposure of immature surface Ig(+) B cells ..
  27. Suen A, Baldwin T. Proapoptotic protein Bim is differentially required during thymic clonal deletion to ubiquitous versus tissue-restricted antigens. Proc Natl Acad Sci U S A. 2012;109:893-8 pubmed publisher
    ..However, in the case of ubiquitous self-antigens (UbA), Bim is not required for the clonal deletion of self-reactive thymocytes, suggesting the existence of nonapoptotic clonal deletion mechanisms...
  28. Zucchelli S, Holler P, Yamagata T, Roy M, Benoist C, Mathis D. Defective central tolerance induction in NOD mice: genomics and genetics. Immunity. 2005;22:385-96 pubmed
    ..Intersection of the data from the two approaches points to a small set of attractive candidate genes. ..
  29. Baldwin T, Sandau M, Jameson S, Hogquist K. The timing of TCR alpha expression critically influences T cell development and selection. J Exp Med. 2005;202:111-21 pubmed
    ..Collectively, these data establish the importance of proper timing of TCR expression in thymic development and selection and emphasize the need to use models that most accurately reflect the physiologic process. ..
  30. Mayerova D, Hogquist K. Central tolerance to self-antigen expressed by cortical epithelial cells. J Immunol. 2004;172:851-6 pubmed
    ..A predominant mechanism for this is clonal deletion; though receptor editing, anergy induction, and positive selection of regulatory T cells have also been ..
  31. Ota T, Ota M, Duong B, Gavin A, Nemazee D. Liver-expressed Igkappa superantigen induces tolerance of polyclonal B cells by clonal deletion not kappa to lambda receptor editing. J Exp Med. 2011;208:617-29 pubmed publisher
    ..superantigen ubiquitously, in which ? cells edit efficiently to ?, in pAlb mice, ? B cells underwent clonal deletion. Their ? cells failed to populate lymph nodes, and the remaining splenic ? cells were anergic, arrested at a ..
  32. Wirnsberger G, Hinterberger M, Klein L. Regulatory T-cell differentiation versus clonal deletion of autoreactive thymocytes. Immunol Cell Biol. 2011;89:45-53 pubmed publisher
    The concept of clonal deletion of immune cells that carry an autoreactive antigen receptor was a central prediction of Burnet's clonal selection theory...
  33. Kroger C, Flores R, Morillon M, Wang B, Tisch R. Dysregulation of thymic clonal deletion and the escape of autoreactive T cells. Arch Immunol Ther Exp (Warsz). 2010;58:449-57 pubmed publisher
    ..In this review, mechanisms that regulate the efficacy of negative selection and influence the deletion of autoreactive thymocytes will be discussed. ..
  34. Buhlmann J, Elkin S, Sharpe A. A role for the B7-1/B7-2:CD28/CTLA-4 pathway during negative selection. J Immunol. 2003;170:5421-8 pubmed
    ..Finally, CTLA-4 delivers signals that inhibit selection, suggesting that CTLA-4 and CD28 have opposing functions in thymic development. Combined, the data demonstrate that B7-1/B7-2-dependent signals help shape the T cell repertoire. ..
  35. Rathmell J, Cooke M, Ho W, Grein J, Townsend S, Davis M, et al. CD95 (Fas)-dependent elimination of self-reactive B cells upon interaction with CD4+ T cells. Nature. 1995;376:181-4 pubmed
    ..These findings identify a novel regulatory step for eliminating autoreactive B cells that seems unique in its dependence on CD95. ..
  36. Mingueneau M, Jiang W, Feuerer M, Mathis D, Benoist C. Thymic negative selection is functional in NOD mice. J Exp Med. 2012;209:623-37 pubmed publisher
    ..isolated and preselected thymocytes, we show that nonobese diabetic (NOD) genetic variation impairs neither clonal deletion nor downstream transcriptional programs...
  37. McCaughtry T, Baldwin T, Wilken M, Hogquist K. Clonal deletion of thymocytes can occur in the cortex with no involvement of the medulla. J Exp Med. 2008;205:2575-84 pubmed publisher
    ..T cell receptor for antigen (TCR) expression is appropriately timed and a ubiquitous self-antigen drives clonal deletion in male mice. We demonstrated unambiguously that this deletion event occurs in the thymic cortex...
  38. Mandik Nayak L, Ridge N, Fields M, Park A, Erikson J. Role of B cells in systemic lupus erythematosus and rheumatoid arthritis. Curr Opin Immunol. 2008;20:639-45 pubmed publisher
    ..tolerance to many self-proteins is actively maintained by either purging self-reactive B receptors through clonal deletion and receptor editing, or by functional silencing known as anergy...
  39. Halverson R, Torres R, Pelanda R. Receptor editing is the main mechanism of B cell tolerance toward membrane antigens. Nat Immunol. 2004;5:645-50 pubmed
    ..autoantigens are eliminated in the bone marrow by two mechanisms of tolerance: receptor editing and clonal deletion. However, the relative contributions of clonal deletion and receptor editing to B cell tolerance in a ..
  40. Hernandez J, Aung S, Redmond W, Sherman L. Phenotypic and functional analysis of CD8(+) T cells undergoing peripheral deletion in response to cross-presentation of self-antigen. J Exp Med. 2001;194:707-17 pubmed
    ..These data demonstrate that the recognition by naive CD8(+) T cells of cross-presented self-antigen results in localized proliferation and deletion, without the production of effector cells. ..
  41. Kishimoto H, Sprent J. A defect in central tolerance in NOD mice. Nat Immunol. 2001;2:1025-31 pubmed
    ..In light of these findings, disease onset in NOD mice may reflect defects in central as well as peripheral tolerance. ..
  42. Liston A, Gray D, Lesage S, Fletcher A, Wilson J, Webster K, et al. Gene dosage--limiting role of Aire in thymic expression, clonal deletion, and organ-specific autoimmunity. J Exp Med. 2004;200:1015-26 pubmed
  43. Kenny J, Rezanka L, Lustig A, Fischer R, Yoder J, Marshall S, et al. Autoreactive B cells escape clonal deletion by expressing multiple antigen receptors. J Immunol. 2000;164:4111-9 pubmed
    ..They were 1) developmentally arrested in the bone marrow, 2) unable to secrete Ab, 3) able to escape clonal deletion and develop into B1 B cells in the peritoneal cavity, and 4) rescued by overexpression of bcl-2...
  44. Klein L, Kyewski B. Self-antigen presentation by thymic stromal cells: a subtle division of labor. Curr Opin Immunol. 2000;12:179-86 pubmed
  45. Green D. The suicide in the thymus, a twisted trail. Nat Immunol. 2003;4:207-8 pubmed
  46. Buch T, Rieux Laucat F, Forster I, Rajewsky K. Failure of HY-specific thymocytes to escape negative selection by receptor editing. Immunity. 2002;16:707-18 pubmed
    ..In the absence of the restricting MHC element, however, developing thymocytes replaced the inserted TCR alpha exon efficiently. ..
  47. van Santen H, Benoist C, Mathis D. Number of T reg cells that differentiate does not increase upon encounter of agonist ligand on thymic epithelial cells. J Exp Med. 2004;200:1221-30 pubmed
    ..much less sensitive than their CD4+CD25- companions, by two to three orders of magnitude, to agonist-induced clonal deletion, such that their proportion increased, giving the false impression of induced differentiation...
  48. Cho H, Edmondson S, Miller A, Sellars M, Alexander S, Somersan S, et al. Cutting edge: identification of the targets of clonal deletion in an unmanipulated thymus. J Immunol. 2003;170:10-3 pubmed
    Autoreactive thymocytes can be eliminated by clonal deletion during their development in the thymus...
  49. Sonenshein G. Down-modulation of c-myc expression induces apoptosis of B lymphocyte models of tolerance via clonal deletion. J Immunol. 1997;158:1994-7 pubmed
    ..recent evidence demonstrating that inhibition of c-myc expression activates apoptosis of B cell models of clonal deletion and that rescue from apoptosis by CD40 ligand leads to maintenance of c-Myc levels...
  50. Serreze D, Choisy Rossi C, Grier A, Holl T, Chapman H, Gahagan J, et al. Through regulation of TCR expression levels, an Idd7 region gene(s) interactively contributes to the impaired thymic deletion of autoreactive diabetogenic CD8+ T cells in nonobese diabetic mice. J Immunol. 2008;180:3250-9 pubmed
    ..These findings provide further insight to how susceptibility genes, both within and outside the MHC, may interact to elicit autoreactive T cell responses mediating T1D development in both NOD mice and human patients. ..
  51. Palmer E. Negative selection--clearing out the bad apples from the T-cell repertoire. Nat Rev Immunol. 2003;3:383-91 pubmed
    ..This review discusses several cellular and molecular aspects of negative selection. ..
  52. Bonasio R, Scimone M, Schaerli P, Grabie N, Lichtman A, von Andrian U. Clonal deletion of thymocytes by circulating dendritic cells homing to the thymus. Nat Immunol. 2006;7:1092-100 pubmed
    ..These findings identify a migratory route by which peripheral DCs may contribute to central tolerance. ..
  53. Zhan Y, Purton J, Godfrey D, Cole T, Heath W, Lew A. Without peripheral interference, thymic deletion is mediated in a cohort of double-positive cells without classical activation. Proc Natl Acad Sci U S A. 2003;100:1197-202 pubmed
    ..Thus, negative selection represents an "abortive" activation different from activation-induced cell death of mature T cells. ..