Skip to main content
PMC home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1990 Oct;87(19):7727–7731. doi: 10.1073/pnas.87.19.7727

Evidence for susceptibility of intrathymic T-cell precursors and their progeny carrying T-cell antigen receptor phenotypes TCR alpha beta + and TCR gamma delta + to human immunodeficiency virus infection: a mechanism for CD4+ (T4) lymphocyte depletion.

S M Schnittman 1, S M Denning 1, J J Greenhouse 1, J S Justement 1, M Baseler 1, J Kurtzberg 1, B F Haynes 1, A S Fauci 1
PMCID: PMC54821  PMID: 2217206

Abstract

Individuals infected by the human immunodeficiency virus type 1 (HIV-1) demonstrate progressive depletion and qualitative dysfunction of the helper T4 (CD4+) cell population. Mechanisms proposed for attrition of CD4+ T cells include direct cytopathicity of these mature cells following infection as well as infection of early T-lymphocyte progenitors. The latter mechanism could lead to failure to regenerate mature functioning CD4+ T cells. The present study determines the susceptibility of thymocytes at various stages of maturity to infection with HIV-1. Various normal thymocyte populations were inoculated with HIV-1, including unfractionated (UF), CD3- CD4- CD8- ["triple negative" (TN)], CD4+ CD8+ ["double positive" (DP)] thymocytes, and thymocyte populations obtained by limited dilution cloning. Cultures were studied for the presence of HIV-1 DNA by polymerase chain reaction in addition to examination for reverse transcriptase activity. We determined that transformed T-cell and thymocyte cell lines completely lacking CD4 were not susceptible to infection by HIV-1, whereas all of the following lines were: UF thymocytes (70-90% CD4hi+); DP thymocytes (99% CD4hi+); TN thymocytes (0% CD4hi+); and TCR alpha beta +, TCR gamma delta +, or CD16+ CD3- (natural killer) thymocyte clones expressing variable levels of CD4 and representing the progeny of TN thymocytes. [TCR alpha beta + and TCR gamma delta + refer to the chains of the T-cell antigen receptor (TCR), and CD4hi refers to a strong rightward shift (greater than 30 linear channels) of the CD4 curve on flow cytometric analysis compared with control.] Monoclonal antibodies (mAbs) to CD4 (T4a epitope) but not to CD3 (T3) were capable of blocking infection of mature and immature CD4hi+ thymocytes. Moreover, anti-CD4(T4a) mAbs also inhibited infection of CD4hi- TN thymocytes, indicating that these T-cell precursors--despite their apparent "triple negativity" (CD3- CD4hi- CD8-)--expressed sufficient CD4 molecules to become infected. Cell sorter analysis with a panel of CD4 mAbs demonstrated a mean shift of the mean fluorescence channel (MFC) with CD4 mAbs on TN thymocytes of 6 +/- 4 MFC units. Thus, intrathymic T-cell precursors and their progeny representing many stages of T-cell ontogeny are susceptible to infection by HIV-1, including early TN thymocytes, which express very low levels of CD4. Infection of multiple stages and multiple subsets of the T-cell lineage in man, mediated via the CD4 molecule, may explain the inability of the T-cell pool to regenerate in the setting of progressive HIV infection.

Full text

PDF
7727

Images in this article

7729Image
on p.7729
7729Image
on p.7729
7729Image
on p.7729
7730Image
on p.7730

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Aparicio P., Alonso J. M., Toribio M. L., Marcos M. A., Pezzi L., Martínez-A C. Isolation and characterization of (gamma, delta) CD4+ T cell clones derived from human fetal liver cells. J Exp Med. 1989 Sep 1;170(3):1009–1014. doi: 10.1084/jem.170.3.1009. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bowen D. L., Lane H. C., Fauci A. S. Immunopathogenesis of the acquired immunodeficiency syndrome. Ann Intern Med. 1985 Nov;103(5):704–709. doi: 10.7326/0003-4819-103-5-704. [DOI] [PubMed] [Google Scholar]
  3. Brenner M. B., McLean J., Dialynas D. P., Strominger J. L., Smith J. A., Owen F. L., Seidman J. G., Ip S., Rosen F., Krangel M. S. Identification of a putative second T-cell receptor. Nature. 1986 Jul 10;322(6075):145–149. doi: 10.1038/322145a0. [DOI] [PubMed] [Google Scholar]
  4. Denning S. M., Kurtzberg J., Leslie D. S., Haynes B. F. Human postnatal CD4- CD8- CD3- thymic T cell precursors differentiate in vitro into T cell receptor delta-bearing cells. J Immunol. 1989 May 1;142(9):2988–2997. [PubMed] [Google Scholar]
  5. Fauci A. S. Current issues in developing a strategy for dealing with the acquired immunodeficiency syndrome. Proc Natl Acad Sci U S A. 1986 Dec;83(24):9278–9283. doi: 10.1073/pnas.83.24.9278. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Fauci A. S., Masur H., Gelmann E. P., Markham P. D., Hahn B. H., Lane H. C. NIH conference. The acquired immunodeficiency syndrome: an update. Ann Intern Med. 1985 Jun;102(6):800–813. doi: 10.7326/0003-4819-102-6-800. [DOI] [PubMed] [Google Scholar]
  7. Fauci A. S. The human immunodeficiency virus: infectivity and mechanisms of pathogenesis. Science. 1988 Feb 5;239(4840):617–622. doi: 10.1126/science.3277274. [DOI] [PubMed] [Google Scholar]
  8. Ferrick D. A., Ohashi P. S., Wallace V., Schilham M., Mak T. W. Thymic ontogeny and selection of alpha beta and gamma delta T cells. Immunol Today. 1989 Dec;10(12):403–407. doi: 10.1016/0167-5699(89)90035-2. [DOI] [PubMed] [Google Scholar]
  9. Folks T., Benn S., Rabson A., Theodore T., Hoggan M. D., Martin M., Lightfoote M., Sell K. Characterization of a continuous T-cell line susceptible to the cytopathic effects of the acquired immunodeficiency syndrome (AIDS)-associated retrovirus. Proc Natl Acad Sci U S A. 1985 Jul;82(13):4539–4543. doi: 10.1073/pnas.82.13.4539. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Grody W. W., Fligiel S., Naeim F. Thymus involution in the acquired immunodeficiency syndrome. Am J Clin Pathol. 1985 Jul;84(1):85–95. doi: 10.1093/ajcp/84.1.85. [DOI] [PubMed] [Google Scholar]
  11. Harper M. E., Marselle L. M., Gallo R. C., Wong-Staal F. Detection of lymphocytes expressing human T-lymphotropic virus type III in lymph nodes and peripheral blood from infected individuals by in situ hybridization. Proc Natl Acad Sci U S A. 1986 Feb;83(3):772–776. doi: 10.1073/pnas.83.3.772. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Haynes B. F., Denning S. M., Le P. T., Singer K. H. Human intrathymic T cell differentiation. Semin Immunol. 1990 Jan;2(1):67–77. [PubMed] [Google Scholar]
  13. Haynes B. F., Denning S. M., Singer K. H., Kurtzberg J. Ontogeny of T-cell precursors: a model for the initial stages of human T-cell development. Immunol Today. 1989 Mar;10(3):87–91. doi: 10.1016/0167-5699(89)90232-6. [DOI] [PubMed] [Google Scholar]
  14. Hedrick S. M., Nielsen E. A., Kavaler J., Cohen D. I., Davis M. M. Sequence relationships between putative T-cell receptor polypeptides and immunoglobulins. Nature. 1984 Mar 8;308(5955):153–158. doi: 10.1038/308153a0. [DOI] [PubMed] [Google Scholar]
  15. Hershfield M. S., Kurtzberg J., Harden E., Moore J. O., Whang-Peng J., Haynes B. F. Conversion of a stem cell leukemia from a T-lymphoid to a myeloid phenotype induced by the adenosine deaminase inhibitor 2'-deoxycoformycin. Proc Natl Acad Sci U S A. 1984 Jan;81(1):253–257. doi: 10.1073/pnas.81.1.253. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Ho D. D., Pomerantz R. J., Kaplan J. C. Pathogenesis of infection with human immunodeficiency virus. N Engl J Med. 1987 Jul 30;317(5):278–286. doi: 10.1056/NEJM198707303170505. [DOI] [PubMed] [Google Scholar]
  17. Hoxie J. A., Alpers J. D., Rackowski J. L., Huebner K., Haggarty B. S., Cedarbaum A. J., Reed J. C. Alterations in T4 (CD4) protein and mRNA synthesis in cells infected with HIV. Science. 1986 Nov 28;234(4780):1123–1127. doi: 10.1126/science.3095925. [DOI] [PubMed] [Google Scholar]
  18. Joshi V. V., Oleske J. M. Pathologic appraisal of the thymus gland in acquired immunodeficiency syndrome in children. A study of four cases and a review of the literature. Arch Pathol Lab Med. 1985 Feb;109(2):142–146. [PubMed] [Google Scholar]
  19. Klatzmann D., Barré-Sinoussi F., Nugeyre M. T., Danquet C., Vilmer E., Griscelli C., Brun-Veziret F., Rouzioux C., Gluckman J. C., Chermann J. C. Selective tropism of lymphadenopathy associated virus (LAV) for helper-inducer T lymphocytes. Science. 1984 Jul 6;225(4657):59–63. doi: 10.1126/science.6328660. [DOI] [PubMed] [Google Scholar]
  20. Klatzmann D., Champagne E., Chamaret S., Gruest J., Guetard D., Hercend T., Gluckman J. C., Montagnier L. T-lymphocyte T4 molecule behaves as the receptor for human retrovirus LAV. Nature. 1984 Dec 20;312(5996):767–768. doi: 10.1038/312767a0. [DOI] [PubMed] [Google Scholar]
  21. Kurtzberg J., Bigner S. H., Hershfield M. S. Establishment of the DU.528 human lymphohemopoietic stem cell line. J Exp Med. 1985 Nov 1;162(5):1561–1578. doi: 10.1084/jem.162.5.1561. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Kurtzberg J., Waldmann T. A., Davey M. P., Bigner S. H., Moore J. O., Hershfield M. S., Haynes B. F. CD7+, CD4-, CD8- acute leukemia: a syndrome of malignant pluripotent lymphohematopoietic cells. Blood. 1989 Feb;73(2):381–390. [PubMed] [Google Scholar]
  23. Kwok S., Mack D. H., Mullis K. B., Poiesz B., Ehrlich G., Blair D., Friedman-Kien A., Sninsky J. J. Identification of human immunodeficiency virus sequences by using in vitro enzymatic amplification and oligomer cleavage detection. J Virol. 1987 May;61(5):1690–1694. doi: 10.1128/jvi.61.5.1690-1694.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Lane H. C., Fauci A. S. Immunologic abnormalities in the acquired immunodeficiency syndrome. Annu Rev Immunol. 1985;3:477–500. doi: 10.1146/annurev.iy.03.040185.002401. [DOI] [PubMed] [Google Scholar]
  25. Lasky L. A., Nakamura G., Smith D. H., Fennie C., Shimasaki C., Patzer E., Berman P., Gregory T., Capon D. J. Delineation of a region of the human immunodeficiency virus type 1 gp120 glycoprotein critical for interaction with the CD4 receptor. Cell. 1987 Sep 11;50(6):975–985. doi: 10.1016/0092-8674(87)90524-1. [DOI] [PubMed] [Google Scholar]
  26. Marrack P., Kappler J. The T cell receptor. Science. 1987 Nov 20;238(4830):1073–1079. doi: 10.1126/science.3317824. [DOI] [PubMed] [Google Scholar]
  27. McDougal J. S., Mawle A., Cort S. P., Nicholson J. K., Cross G. D., Scheppler-Campbell J. A., Hicks D., Sligh J. Cellular tropism of the human retrovirus HTLV-III/LAV. I. Role of T cell activation and expression of the T4 antigen. J Immunol. 1985 Nov;135(5):3151–3162. [PubMed] [Google Scholar]
  28. Ou C. Y., Kwok S., Mitchell S. W., Mack D. H., Sninsky J. J., Krebs J. W., Feorino P., Warfield D., Schochetman G. DNA amplification for direct detection of HIV-1 in DNA of peripheral blood mononuclear cells. Science. 1988 Jan 15;239(4837):295–297. doi: 10.1126/science.3336784. [DOI] [PubMed] [Google Scholar]
  29. Palacios R., Pelkonen J. Prethymic and intrathymic mouse T-cell progenitors. Growth requirements and analysis of the expression of genes encoding TCR/T3 components and other T-cell-specific molecules. Immunol Rev. 1988 Aug;104:5–27. doi: 10.1111/j.1600-065x.1988.tb00757.x. [DOI] [PubMed] [Google Scholar]
  30. Psallidopoulos M. C., Schnittman S. M., Thompson L. M., 3rd, Baseler M., Fauci A. S., Lane H. C., Salzman N. P. Integrated proviral human immunodeficiency virus type 1 is present in CD4+ peripheral blood lymphocytes in healthy seropositive individuals. J Virol. 1989 Nov;63(11):4626–4631. doi: 10.1128/jvi.63.11.4626-4631.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Savino W., Dardenne M., Marche C., Trophilme D., Dupuy J. M., Pekovic D., Lapointe N., Bach J. F. Thymic epithelium in AIDS. An immunohistologic study. Am J Pathol. 1986 Feb;122(2):302–307. [PMC free article] [PubMed] [Google Scholar]
  32. Schnittman S. M., Lane H. C., Roth J., Burrows A., Folks T. M., Kehrl J. H., Koenig S., Berman P., Fauci A. S. Characterization of GP120 binding to CD4 and an assay that measures ability of sera to inhibit this binding. J Immunol. 1988 Dec 15;141(12):4181–4186. [PubMed] [Google Scholar]
  33. Schnittman S. M., Psallidopoulos M. C., Lane H. C., Thompson L., Baseler M., Massari F., Fox C. H., Salzman N. P., Fauci A. S. The reservoir for HIV-1 in human peripheral blood is a T cell that maintains expression of CD4. Science. 1989 Jul 21;245(4915):305–308. doi: 10.1126/science.2665081. [DOI] [PubMed] [Google Scholar]
  34. Schuurman H. J., Krone W. J., Broekhuizen R., van Baarlen J., van Veen P., Golstein A. L., Huber J., Goudsmit J. The thymus in acquired immune deficiency syndrome. Comparison with other types of immunodeficiency diseases, and presence of components of human immunodeficiency virus type 1. Am J Pathol. 1989 Jun;134(6):1329–1338. [PMC free article] [PubMed] [Google Scholar]
  35. Seemayer T. A., Laroche A. C., Russo P., Malebranche R., Arnoux E., Guérin J. M., Pierre G., Dupuy J. M., Gartner J. G., Lapp W. S. Precocious thymic involution manifest by epithelial injury in the acquired immune deficiency syndrome. Hum Pathol. 1984 May;15(5):469–474. doi: 10.1016/s0046-8177(84)80082-9. [DOI] [PubMed] [Google Scholar]
  36. Yanagi Y., Yoshikai Y., Leggett K., Clark S. P., Aleksander I., Mak T. W. A human T cell-specific cDNA clone encodes a protein having extensive homology to immunoglobulin chains. Nature. 1984 Mar 8;308(5955):145–149. doi: 10.1038/308145a0. [DOI] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES