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. 1988 Feb 1;167(2):243–261. doi: 10.1084/jem.167.2.243

DY determinants, possibly associated with novel class II molecules, stimulate autoreactive CD4+ T cells with suppressive activity

PMCID: PMC2188840  PMID: 2450156

Abstract

A set of T cell clones (TCC) isolated from HLA-DR-, Dw-, DQ-matched allogeneic MLCs was found to proliferate autonomously when stimulated with cells carrying a wide range of class I or II specificities. This apparently unrestricted proliferation was relatively weak, and only low levels of IL-2 were present in the supernatants of stimulated cells. Autologous as well as allogeneic PBMC and B lymphoblastoid cell lines (B-LCL) were capable of stimulating such clones, which were also restimulated by suppressive, but not by helper, TCC. Moreover, such clones displayed the unusual property of autostimulation. mAb inhibition experiments suggested that class II- or class II-restricted antigens were involved in stimulation. Thus, certain "broad" mAbs (TU39, SG520) reacting with multiple locus products inhibited activation of these reagents, but none of those reacting more specifically with DR (TU34, TU37, L243, Q2/70, SG157), DQ (TU22, SPV- L3, Leu 10), or DP (B7/21), or mixtures of these mAbs, were able to do so. Evidence from sequential immunoprecipitation experiments suggested that mAb TU39 bound class II-like molecules other than DR, DQ, and DP on TCC and B-LCL, and it is therefore proposed that such putative novel class II-like molecules may carry the stimulating determinants for these autoreactive clones. DY-reactive clones lacked helper activity for B cells but mediated potent suppressive activity on T cell proliferative responses that was not restricted by the HLA type of the responding cells. Suppressive activity was induced in normal PBMC by such clones, as well as by independent suppressive clones, which was also inhibited only by mAb TU39. These findings lead to the proposal that DY-reactive autostimulatory cells may constitute a self- maintaining suppressive circuit, the level of activity of which would be regulated primarily by the availability of IL-2 in the microenvironment.

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Selected References

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  1. Carra G., Accolla R. S. Structural analysis of human Ia antigens reveals the existence of a fourth molecular subset distinct from DP, DQ, and DR molecules. J Exp Med. 1987 Jan 1;165(1):47–63. doi: 10.1084/jem.165.1.47. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Charron D. J., Lotteau V., Turmel P. Hybrid HLA-DC antigens provide molecular evidence for gene trans-complementation. Nature. 1984 Nov 8;312(5990):157–159. doi: 10.1038/312157a0. [DOI] [PubMed] [Google Scholar]
  3. Chen B. P., DeMars R., Sondel P. M. Presentation of soluble antigen to human T cells by products of multiple HLA-linked loci: analysis of antigen presentation by a panel of cloned, autologous, HLA-mutant Epstein-Barr virus-transformed lymphoblastoid cell lines. Hum Immunol. 1987 Jan;18(1):75–91. doi: 10.1016/0198-8859(87)90114-5. [DOI] [PubMed] [Google Scholar]
  4. Damle N. K., Mohagheghpour N., Kansas G. S., Fishwild D. M., Engleman E. G. Immunoregulatory T cell circuits in man. Identification of a distinct T cell subpopulation of the helper/inducer lineage that amplifies the development of alloantigen-specific suppressor T cells. J Immunol. 1985 Jan;134(1):235–243. [PubMed] [Google Scholar]
  5. Eckels D. D., Zeevi A., Beatty P. G., Flomenberg N., Goyert S., Knowles R. W., Mickelson E., Nepom G. T., Parham P., Pawelec G. ASHI Workshop Summary Report of the Science and Education Subcommittee: structural and functional relationships of human class II MHC molecules. Hum Immunol. 1986 Jan;15(1):68–74. doi: 10.1016/0198-8859(86)90317-4. [DOI] [PubMed] [Google Scholar]
  6. Ey P. L., Prowse S. J., Jenkin C. R. Isolation of pure IgG1, IgG2a and IgG2b immunoglobulins from mouse serum using protein A-sepharose. Immunochemistry. 1978 Jul;15(7):429–436. doi: 10.1016/0161-5890(78)90070-6. [DOI] [PubMed] [Google Scholar]
  7. Fernandez N., Labeta M., Kurpisz M., Solana R., Festenstein H. HLA-DQ molecular heterogeneity in HLA-DR4-Dw4 consanguineous cell lines. Dis Markers. 1986 Jun;4(1-2):191–198. [PubMed] [Google Scholar]
  8. Gershon R. K., Eardley D. D., Durum S., Green D. R., Shen F. W., Yamauchi K., Cantor H., Murphy D. B. Contrasuppression. A novel immunoregulatory activity. J Exp Med. 1981 Jun 1;153(6):1533–1546. doi: 10.1084/jem.153.6.1533. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Hayman M. J., Crumpton M. J. Isolation of glycoproteins from pig lymphocyte plasma membrane using Lens culinaris phytohemagglutinin. Biochem Biophys Res Commun. 1972 May 26;47(4):923–930. doi: 10.1016/0006-291x(72)90581-5. [DOI] [PubMed] [Google Scholar]
  10. Hubbard A. L., Cohn Z. A. The enzymatic iodination of the red cell membrane. J Cell Biol. 1972 Nov;55(2):390–405. doi: 10.1083/jcb.55.2.390. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Lamb J. R., Woody J. N., Hartzman R. J., Eckels D. D. In vitro influenza virus-specific antibody production in man: antigen-specific and HLA-restricted induction of helper activity mediated by cloned human T lymphocytes. J Immunol. 1982 Oct;129(4):1465–1470. [PubMed] [Google Scholar]
  12. Martin A., Eiermann T. H., Tricas L., Goldmann S. F. An autoreactive T cell clone derived after allostimulation in vitro: evidence for recognition of a polymorphic self major histocompatibility complex class II gene product. Transplant Proc. 1987 Feb;19(1 Pt 1):875–877. [PubMed] [Google Scholar]
  13. Morimoto C., Letvin N. L., Distaso J. A., Aldrich W. R., Schlossman S. F. The isolation and characterization of the human suppressor inducer T cell subset. J Immunol. 1985 Mar;134(3):1508–1515. [PubMed] [Google Scholar]
  14. Ohta N., Anichini A., Reinsmoen N. L., Strassmann G., Wernet P., Bach F. H. Analysis of human class II antigens by cloned cytolytic T cell reagents: a study using HLA loss mutant lymphoblastoid cell lines and monoclonal antibodies detecting the HLA-DP product(s). Hum Immunol. 1985 May;13(1):21–32. doi: 10.1016/0198-8859(85)90024-2. [DOI] [PubMed] [Google Scholar]
  15. Pawelec G. P., Shaw S., Ziegler A., Müller C., Wernet P. Differential inhibition of HLA-D- or SB-directed secondary lymphoproliferative responses with monoclonal antibodies detecting human Ia-like determinants. J Immunol. 1982 Sep;129(3):1070–1075. [PubMed] [Google Scholar]
  16. Pawelec G., Schneider E. M., Müller C., Wernet P. HLA-DR-, MB- and novel DC-related determinants restrict purified protein derivative of tuberculin (PPD)-stimulated human T cell proliferation. Eur J Immunol. 1985 Jan;15(1):12–17. doi: 10.1002/eji.1830150104. [DOI] [PubMed] [Google Scholar]
  17. Pawelec G., Schneider E. M., Rehbein A., Balko I., Wernet P. Dissection of suppressor cell generation in vitro. Hum Immunol. 1986 Nov;17(3):343–354. doi: 10.1016/0198-8859(86)90285-5. [DOI] [PubMed] [Google Scholar]
  18. Pawelec G., Schneider E. M., Wernet P. Acquisition of suppressive activity and natural killer-like cytotoxicity by human alloproliferative "helper" T cell clones. J Immunol. 1986 Jan;136(2):402–411. [PubMed] [Google Scholar]
  19. Pawelec G., Schneider E. M., Wernet P. Cloned human T lymphocytes with lymphostimulatory capacity preferentially activate suppressor cells. Eur J Immunol. 1984 Apr;14(4):335–340. doi: 10.1002/eji.1830140411. [DOI] [PubMed] [Google Scholar]
  20. Pawelec G., Wernet P., Rosenlund R., Blaurock M., Schneider E. M. Strong lymphoproliferative suppressive function of PLT clones specific for SB-like antigens. Hum Immunol. 1984 Mar;9(3):145–157. doi: 10.1016/0198-8859(84)90042-9. [DOI] [PubMed] [Google Scholar]
  21. Qvigstad E., Moen T., Thorsby E. T-cell clones with similar antigen specificity may be restricted by DR, MT(DC), or SB class II HLA molecules. Immunogenetics. 1984;19(5):455–460. doi: 10.1007/BF00364648. [DOI] [PubMed] [Google Scholar]
  22. Schneider E. M., Pawelec G., Shi L. R., Bühring H. J., Wernet P. Generation of CD4-positive suppressor T cells from mixed lymphocyte cultures in the presence of interleukin 2 receptor antibody TU69. An in vitro model for transplantation tolerance induction. Transplantation. 1987 Aug;44(2):295–302. doi: 10.1097/00007890-198708000-00023. [DOI] [PubMed] [Google Scholar]
  23. Shackelford D. A., Lampson L. A., Strominger J. L. Separation of three class II antigens from a homozygous human B cell line. J Immunol. 1983 Jan;130(1):289–296. [PubMed] [Google Scholar]
  24. Spits H., Borst J., Giphart M., Coligan J., Terhorst C., De Vries J. E. HLA-DC antigens can serve as recognition elements for human cytotoxic T lymphocytes. Eur J Immunol. 1984 Apr;14(4):299–304. doi: 10.1002/eji.1830140404. [DOI] [PubMed] [Google Scholar]
  25. Tonnelle C., DeMars R., Long E. O. DO beta: a new beta chain gene in HLA-D with a distinct regulation of expression. EMBO J. 1985 Nov;4(11):2839–2847. doi: 10.1002/j.1460-2075.1985.tb04012.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Trowsdale J., Kelly A. The human HLA class II alpha chain gene DZ alpha is distinct from genes in the DP, DQ and DR subregions. EMBO J. 1985 Sep;4(9):2231–2237. doi: 10.1002/j.1460-2075.1985.tb03919.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Wank R., Schendel D. J., Blanco M. E., Dupont B. Secondary MLC responses of primed lymphocytes after selective sensitization to non-HLA-D determinants. Scand J Immunol. 1979;9(6):499–505. doi: 10.1111/j.1365-3083.1979.tb03277.x. [DOI] [PubMed] [Google Scholar]
  28. Wernet P., Schneider E. M., Kalthoff F., Pawelec G. Constitutive functional heterogeneity without detectable somatic mutation of antigen receptor genes in helper T cell clones: possible regulation by novel HLA class II "DY" determinants. Immunol Rev. 1987 Apr;96:109–140. doi: 10.1111/j.1600-065x.1987.tb00512.x. [DOI] [PubMed] [Google Scholar]

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