Journal of Clinical Immunology

, Volume 25, Issue 3, pp 265–274 | Cite as

Post-Natal Ontogenesis of the T-Cell Receptor CD4 and CD8 Vβ Repertoire and Immune Function in Children with DiGeorge Syndrome

  • Caterina Cancrini
  • Maria Luisa Romiti
  • Andrea Finocchi
  • Silvia Di Cesare
  • Patrizia Ciaffi
  • Claudia Capponi
  • Savita Pahwa
  • Paolo Rossi


DiGeorge syndrome (DGS) is a congenital disorder characterized by typical facial features, hypoparatyroidism, conotruncal cardiac defects and thymic hypoplasia. Although there are some reports addressing lymphocytes counts and function in DGS children over time, few data have been reported on the T-cell receptor Vβ (TCRBV) repertoire in relation to disease progression. The aim of this study was to evaluate the degree and nature of immunodeficiency and to investigate a possible correlation to clinical findings.

We used third complementary region (CDR3) size spectratyping as a tool for monitoring T-cell repertoire diversity in 7 DGS’s children. The rate of thymic output, the phenotype and function of peripheral T-cells and the humoral immunity were also investigated. At baseline a profound alteration of the TCR repertoire was noted, mainly in the CD8+ T-cells, in DGS patients when compared to a control group. Furthermore, analysis of thymic output showed a significant decrease in TCR rearrangement excision circles (TRECs) levels in the patient group. Immunoglobulin abnormalities were also detected. The observed TCR repertoire alterations, although not statistically significant, may suggest an increased susceptibility to infections. A parallel increase in the TCR repertoire diversity and clinical improvement occurred during the follow-up. Our results confirm that the extent of immunodeficiency is highly variable and could improve through childhood, and indicate that TCR repertoire may be a useful marker to clinically monitor thymic function in this primary immunodeficiency.

Key Words

DiGeorge syndrome TCR repertoire spectratyping TRECs recurrent infections 


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  1. 1.
    DiGeorge A: Congenital absence of the thymus and its immunologic consequences: Concurrence with congenital hypoparatyroidism. In Immunologic Deficiency Diseases in Man Birth Defects Original Article Series, RA Good, D Bergsma (eds). New York, New York National Foundation Press, 4:116–121, 1968Google Scholar
  2. 2.
    Hong R: The Di George anomaly. Immunodef Rev 3:1–14, 1991PubMedGoogle Scholar
  3. 3.
    Driscoll DA, Spinner NB, Budarf ML, McDonald-McGinn DM, Zackai EH, Goldberg RB, Shptintzen RJ, Saal HM, Zonana J, Jones MC, Mascarello JT, Emanuel BS: Deletions and microdeletions of 22q11.2 in velo-cardio-facial syndrome. Am J Med Genet 44:261–268, 1992CrossRefPubMedGoogle Scholar
  4. 4.
    Driscoll DA, Budarf ML, Emanuel BS: A genetic etiology for DiGeorge syndrome: Consistent deletions and microdeletions of 22q11. Am J Hum Genet 5:933, 1992Google Scholar
  5. 5.
    Perez E, Sullivan KE: Chromosome 22q11.2 deletion sindrome (Di George and velocardiofaciel syndromes). Curr Opin Pediatr 14:678–683, 2002CrossRefPubMedGoogle Scholar
  6. 6.
    Barrett DJ, Ammann AJ, Wara DW, Cowan MJ, Fisher TJ, Stiehm ER: Clinical and immunologic spectrum of the DiGeorge syndrome. J Clin Lab Immunol 6:1–6, 1981PubMedGoogle Scholar
  7. 7.
    Bastian J, Law S, Vogler L, Lawton A, Herrod H, Anderson S, Horowitz S, Hong R: Prediction of persistent immunodeficiency in the DiGeorge anomaly. J Pediatr 115:391–396, 1989PubMedGoogle Scholar
  8. 8.
    Muller W, Peter HH, Wilken M, Juppner H, Kallfelz HC, Krohn HP, Miller K, Rieger CH: The DiGeorge syndrome. Clinical evaluation and course of partial and complete forms of the syndrome. Eur J Pediatr 147:496–502, 1988CrossRefPubMedGoogle Scholar
  9. 9.
    Sullivan KE, Jawad AF, Randall P, Driscoll DA, Emanuel BS, McDonald-McGinn DM, Xackai EH: Lack of correlation between impaired T-cell production, immunodeficiency, and other phenotypic features in chromosome 22q11.2 deletion syndromes. Clin Immunol Immunopathol 86:141–146, 1998CrossRefPubMedGoogle Scholar
  10. 10.
    Sirianni MC, Businco L, Fiore L, Seminara R, Aiuti F: T-cell subsets and natural killer cells in DiGeorge and SCID patients. Birth Defects Orig Artic Ser 19:107–108, 1983Google Scholar
  11. 11.
    Goldsobel AB, HaasA, Stiem ER: Bone marrow transplantation in DiGeorge syndrome. J Pediatr 111:40–44, 1987PubMedGoogle Scholar
  12. 12.
    Borzy MS, Ridgway D, Noya FJ, Shearer WT: Successful bone marrow transplantation with split chimerism in DiGeorge syndrome. J Clin Immunol 9:386–392, 1989CrossRefPubMedGoogle Scholar
  13. 13.
    Matsumoto T, Amamoto N, Kondoh T, Nakayama M, Takayanagi T, Tsuji Y: Complete-type DiGeorge syndrome treated by bone marrow transplantation. Bone Marrow Transplant 22:927–930, 1998CrossRefPubMedGoogle Scholar
  14. 14.
    Markert ML, Boeck A, Hale LP, Kloster AL, McLaughlin TM, Batchvarova MN, Douek DC, Koup RA, Kostyu DD, Ward FE, Rice HE, Mahaffey SM, Schiff SE, Buckley RH, Haynes BF: Transplantation of thymus tissue in complete DiGeorge syndrome. N Engl J Med 341:1180–1189, 1999CrossRefPubMedGoogle Scholar
  15. 15.
    Markert ML, Sarzotti M, Ozaki DA, Sempowski GD, Rhein ME, Hale LP, Le Deist F, Alexieff MJ, Li J, Hauser ER, Haynes BF, Rice HE, Skinner MA, Mahaffey SM, Jaggers J, Stein LD, Mill MR: Thymus transplantation in complete DiGeorge syndrome: Immunologic and safety evaluations in 12 patients. Blood 102:1121–1130, 2003CrossRefPubMedGoogle Scholar
  16. 16.
    Markert ML, Alexieff MJ, Li J, Sarzotti M, Ozaki DA, Devlin BH, Sedlak DA, Sempowski GD, Hale LP, Rice HE, Mahaffey SM, Skinner MA: Postnatal thymus transplantation with immunosuppression as treatment for DiGeorge syndrome. Blood 104:2574–2581, 2004CrossRefPubMedGoogle Scholar
  17. 17.
    Markert ML, Hummell DS, Rosenblatt HM, Schiff SE, Harville TO, Williams LW, Schiff RI, Buckley RH: Complete DiGeorge syndrome: Persistence of profound immunodeficiency. J Pediatr 132:15–21, 1998PubMedGoogle Scholar
  18. 18.
    Jawad AF, McDonald-McGinn D, Zackai E, Sullivan KE: Immunologic features of chromosome 22q11.2 deletion syndrome (DiGeorge syndrome/velocardiofacial syndrome). J Pediatr 139:715–723, 2001CrossRefPubMedGoogle Scholar
  19. 19.
    Sullivan KE, McDonald-McGinn D, Driscoll DA, Emanuel BS, Zackai EH, Jawad AF: Longitudinal analysis of lymphocyte function and numbers in the first year of life in chromosome 22q11.2 deletion syndrome (DiGeorge syndrome/velocardiofacial syndrome). Clin Diagn Lab Immunol 6:906–911, 1999PubMedGoogle Scholar
  20. 20.
    Gorski J, Yassai M, Zhu X, Kissela B, Keever C, Flomberg N: Circulating T-cell repertoire complexity in normal individuals and bone marrow recipients analyzed by CDR3 size spectratyping. Correlation with immune status. J Immunol 152:5109–5119, 1994PubMedGoogle Scholar
  21. 21.
    Pannetier C, Even J, Kourilsky P: T-cell repertoire diversity and clonal expansions in normal and clinical samples. Immunol Today 16:176–181, 1995CrossRefPubMedGoogle Scholar
  22. 22.
    Choi Y, Kotzin B, Herron L, Callan J, Marack P, Kappler J: Interaction of Staphylococcus aureus toxin “suoerantigens” with human T-cells. Proc Natl Acad Sci USA 86:8941–8945, 1989PubMedGoogle Scholar
  23. 23.
    Halapi E, Jeddi-Tehrani M, Blucher A, Andersson R, Rossi P, Wigzell H, Grinewald J: Diverse T-cell receptor CDR3 length patterns in human CD4+ and CD8+T lymphocytes from newborns and adults. Scand J Immunol Feb 49–54, 1999Google Scholar
  24. 24.
    Douek DC, McFarland RD, Keiser PH, Gage EA, Massey JM, Haynes BF, Polis MA, Haase AT, Feinberg MB, Sullivan JL, Jamieson BD, Zack JA, Picker LJ, Koup RA: Changes in thymic function with age and during the treatment of HIV infection. Nature 396:6906–6995, 1998Google Scholar
  25. 25.
    Markert ML, Alexieff MJ, Li J, Sarzotti M, Ozaki DA, Devlin BH, Sempowski GD, Rhein ME, Szabolcs P, Hale LP, Buckley RH, Coyne KE, Rice HE, Mahaffey SM, Skinner MA: Complete DiGeorge syndrome: Development of rash, lymphadenopathy, and oligoclonal T-cells in 5 cases. J Allergy Clin Immunol 113:734–741, 2004CrossRefPubMedGoogle Scholar
  26. 26.
    Piliero LM, Sanford AN, McDonald-McGinn DM, Zackai EH, Sullivan KE: T-cell homeostasis in humans with thymic hypoplasia due to chromosome 22q11.2 deletion syndrome. Blood 103:1020–1025, 2004CrossRefPubMedGoogle Scholar
  27. 27.
    Pierdominici M, Mazzetta F, Caprini M, Marziali M, Digilio MC, Marino B, Aiuti A, Amati F, Russo C, Novelli G, Pandolfi F, Luzi G, Giovanetti A: Biased T-cell receptor repertoires in patients with chromosome 22q11.2 deletion syndrome (Di George syndrome/velocardiofacial syndrome). Clin Exp Immunol 132:323–331, 2003CrossRefPubMedGoogle Scholar
  28. 28.
    Masci AM, Palmieri G, Perna F, Montella L, Merkabaoui G, Sacerdoti G, Martinetti A, Racioppi L: Immunological findings in thymoma and thymoma-related syndromes. Ann Med 31:86–89, 1999PubMedGoogle Scholar
  29. 29.
    Pignata C, Gaetaniello L, Masci AM, Frank J, Christiano A, Matrecano E, Racioppi L: Human equivalent of the mouse Nude/SCID phenotype: Long-term evaluation of immunologic reconstitution after bone marrow transplantation. Blood 97:880–885, 1999CrossRefGoogle Scholar
  30. 30.
    Signorini S, Pirovano S, Fiorentini S, Stellini R, Bianchi V, Albertini A, Imberti L: Restriction of T-cell receptor repertoires in idiopathic CD4+ lymphocytopenia. Br J Haematol 110:434–437, 2000CrossRefPubMedGoogle Scholar
  31. 31.
    Brooks EG, Filipovich AH, Padgett JW, Mamlock R, Goldblum RM: T-cell receptor analysis in Omenn’s syndrome: Evidence for defects in gene rearrangement and assembly. Blood 93:242–250, 1999PubMedGoogle Scholar
  32. 32.
    Callan MF, Steven N, Krausa P, Wilson JD, Moss PA, Gillespie GM, Bell JL, Rickinson AB, McMichael AJ: Large clonal expansions of CD8+ T-cells in acute infectious mononucleosis. Nat Med 2:906–911, 1996CrossRefPubMedGoogle Scholar
  33. 33.
    Pantaleo G, Soudeyns H, Demarest JF, Vaccarezza M, Graziosi C, Paolucci, Daucher M, Cohen OJ, Denis F, Biddison WE, Sekaly RP, Fauci AS: Evidence for rapid disappearance of initially expanded HIV-specific CD8+ T-cell clones during primary HIV infection. Proc Natl Acad Sci USA 94:9848–9853, 1997CrossRefPubMedGoogle Scholar
  34. 34.
    Pantaleo G, Demarest JF, Soudeyns H, Graziosi C, Denis F, Adelsberger JW, Borrow P, Saag MS, Shaw GM, Sekaly RP, Fauci AS: Major expansion of CD-8 T-cells with predominant VB usage during the primary immune response to HIV. Nature 370:463–467, 1994CrossRefPubMedGoogle Scholar
  35. 35.
    Halapi E, Gigliotti D, HodaraV, Halapi E, Gigliotti D, Hodara V, Scarlatti G, Tovo PA, DeMaria A, Wigzell H, Rossi P: Detection of CD8 T-cell expansion with restricted T-cell receptor V gene usage in infant vertically infected by HIV-1. AIDS 10:1621–1626, 1996PubMedGoogle Scholar
  36. 36.
    Romiti ML, Cacrini C, Castelli-Gattinara GC, Di Cesare S, Ciaffi P, Bernardi S, De Gasperi MR, Halapi E, Rossi P: Kinetics of the T-cell receptor CD4 and CD8 Vβ repertoire in HIV-1 vertically infected infant early treated with HAART. AIDS 15:2075–2084, 2001CrossRefPubMedGoogle Scholar
  37. 37.
    Khan N, Shariff N, Cobbold M, Bruton R, Ainsworth JA, SinclairAJ, Nayak L, Moss PAM: Citomegalovirus seropositivity drives CD8 T-cell repertoire toward greater clonality in healthy elderly individuals. J Immunol 169:1984–1992, 2002PubMedGoogle Scholar
  38. 38.
    Serrano D, Becker K, Cunningham-Rundles C, Mayer L: Characterization of the T-cell receptor repertoire in patients with common variable immunodeficiency: oligoclonal expansion of CD8(+) T-cells. Clin Immunol 97:248–258, 2000CrossRefPubMedGoogle Scholar
  39. 39.
    Chavan S, Bennuri B, Kharbanda M, Chandrasekaran A, Bakshi S, Pahwa S: Immune reconstitution following antiretroviral therapy in HIV-infected children: Involvement of thymic function. J Infect Dis 183:1445–1454, 2001CrossRefPubMedGoogle Scholar
  40. 40.
    Mayumi M, Kimata H, Suehiro Y, Hosoi S, Ito S, Kuge Y, Shinomiya K, Mikawa H: DiGeorge syndrome with hypogammaglobulinaemia: A patient with excess suppressor T-cell activity treated with fetal thymus transplantation. Eur J Pediatr 149:512–522, 1989Google Scholar
  41. 41.
    Schubert MS, Moss RB: Selective polysaccharide antibody deficiency in familial DiGeorge syndrome. Ann Allergy 69:231–238, 1992PubMedGoogle Scholar
  42. 42.
    Smith CA, Driscoll DA, Emanuel BS, McDonald-McGinn DM, Zackai EH, Sullivan KE: Increased prevalence of immunoglobulin A deficiency in patients with the chromosome 22q11.2 deletion syndrome (DiGeorge syndrome/velocardiofacial syndrome). Clin Diagn Lab Immunol 5:415–417, 1998PubMedGoogle Scholar
  43. 43.
    Gennery AR, Barge D, O’Sullivan JJ, Flood TJ, Abinun M, Cant AJ: Antibody deficiency and autoimmunity in 22q11.2 deletion syndrome. Arch Dis Child 86:422–425, 2002CrossRefPubMedGoogle Scholar
  44. 44.
    Sarzotti M, Patel DD, Li X, Ozaki DA, Cao S, Langdon S, Parrott RE, Coyne K Buckley RH: T-cell repertoire development in humans with SCID after nonablative allogenic marrow transplantation. J Immunol 170:2711–2718, 2003PubMedGoogle Scholar

Copyright information

© Springer Science + Business Media, Inc. 2005

Authors and Affiliations

  • Caterina Cancrini
    • 1
    • 2
  • Maria Luisa Romiti
    • 1
  • Andrea Finocchi
    • 1
    • 2
  • Silvia Di Cesare
    • 1
  • Patrizia Ciaffi
    • 2
  • Claudia Capponi
    • 2
  • Savita Pahwa
    • 3
  • Paolo Rossi
    • 1
    • 2
    • 4
  1. 1.Chair of Pediatrics, Department of Public HealthUniversity of Tor VergataRomeItaly
  2. 2.Division of Immunology and Infectious DiseasesChildren’s Hospital Bambino GesùRomeItaly
  3. 3.Immunology and Inflammation Center, North Shore LIJ Research InstituteNew York University School of MedicineManhasset
  4. 4.Department of Pediatrics, Department of Immunology and Infectious Disease, Children Hospital Bambino GesùTor Vergata UniversityRomeItaly

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