Skip to main content
NCBI home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1994 Nov 1;180(5):1817–1827. doi: 10.1084/jem.180.5.1817

Anti-SCID mouse reactivity shapes the human CD4+ T cell repertoire in hu-PBL-SCID chimeras

PMCID: PMC2191753  PMID: 7964463

Abstract

Injecting human peripheral blood mononuclear cells into severe combined immunodeficient (SCID) mice results in long-term engraftment of human lymphocytes, of which > 98% are phenotypically mature, activated T cells. Here we have characterized the human T cells that populate such hu-PBL-SCID chimeras. We report that these human T cells do not mobilize Ca2+ after CD3 stimulation, i.e., their T cell receptor (TCR)- mediated signal transduction is deficient. Chimera-derived human T cells do not secrete lymphokines or undergo blastogenesis after CD3 stimulation, but proliferate in response to interleukin 2 (IL-2), defining the chimera derived human T cells as anergic. Anergy was seen in both the CD4+ and the CD8+ subpopulations. We established human T cell lines from chimeras. These T cells retained their anergic state for 1-2 mo in culture, after which they simultaneously regained the ability to mobilize Ca2+, secrete lymphokines, and to undergo blastogenesis following stimulation via the TCR. Once regaining proliferative responsiveness to CD3 stimulation, these CD4+ T cell lines displayed anti-SCID mouse reactivity and showed no specificity for recall antigens. All CD3-responsive CD4+ T cell clones obtained from such lines were SCID mouse specific, recognizing native major histocompatibility complex class II products on the murine cells. In contrast, chimera-derived human CD8+ cell lines and clones did not display detectable anti-mouse reactivity. The data show that the human T cell system in long term hu-PBL-SCID chimeras is nonfunctional due to both anergy and the limitation of the CD4+ repertoire to xenoreactive clones. The data suggest that long-term hu-PBL-SCID chimerism represents an atypical graft-versus-host reaction in which the human effector T cells become anergic in the murine environment.

Full Text

The Full Text of this article is available as a PDF (1.1 MB).

Selected References

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

  1. Abrams J. S., Roncarolo M. G., Yssel H., Andersson U., Gleich G. J., Silver J. E. Strategies of anti-cytokine monoclonal antibody development: immunoassay of IL-10 and IL-5 in clinical samples. Immunol Rev. 1992 Jun;127:5–24. doi: 10.1111/j.1600-065x.1992.tb01406.x. [DOI] [PubMed] [Google Scholar]
  2. Armstrong N., Cigel F., Borcherding W., Hong R., Malkovska V. In vitro preactivated human T cells engraft in SCID mice and migrate to murine lymphoid tissues. Clin Exp Immunol. 1992 Dec;90(3):476–482. doi: 10.1111/j.1365-2249.1992.tb05870.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Barry T. S., Haynes B. F. In vivo models of human lymphopoiesis and autoimmunity in severe combined immune deficient mice. J Clin Immunol. 1992 Sep;12(5):311–324. doi: 10.1007/BF00920788. [DOI] [PubMed] [Google Scholar]
  4. Beverly B., Kang S. M., Lenardo M. J., Schwartz R. H. Reversal of in vitro T cell clonal anergy by IL-2 stimulation. Int Immunol. 1992 Jun;4(6):661–671. doi: 10.1093/intimm/4.6.661. [DOI] [PubMed] [Google Scholar]
  5. Farrar M. A., Schreiber R. D. The molecular cell biology of interferon-gamma and its receptor. Annu Rev Immunol. 1993;11:571–611. doi: 10.1146/annurev.iy.11.040193.003035. [DOI] [PubMed] [Google Scholar]
  6. Gray D., Matzinger P. T cell memory is short-lived in the absence of antigen. J Exp Med. 1991 Nov 1;174(5):969–974. doi: 10.1084/jem.174.5.969. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Hoffmann-Fezer G., Gall C., Zengerle U., Kranz B., Thierfelder S. Immunohistology and immunocytology of human T-cell chimerism and graft-versus-host disease in SCID mice. Blood. 1993 Jun 15;81(12):3440–3448. [PubMed] [Google Scholar]
  8. Hoffmann-Fezer G., Kranz B., Gall C., Thierfelder S. Peritoneal sanctuary for human lymphopoiesis in SCID mice injected with human peripheral blood lymphocytes from Epstein-Barr virus-negative donors. Eur J Immunol. 1992 Dec;22(12):3161–3166. doi: 10.1002/eji.1830221220. [DOI] [PubMed] [Google Scholar]
  9. Jenkins M. K., Mueller D., Schwartz R. H., Carding S., Bottomley K., Stadecker M. J., Urdahl K. B., Norton S. D. Induction and maintenance of anergy in mature T cells. Adv Exp Med Biol. 1991;292:167–176. doi: 10.1007/978-1-4684-5943-2_19. [DOI] [PubMed] [Google Scholar]
  10. Jenkins M. K., Schwartz R. H. Antigen presentation by chemically modified splenocytes induces antigen-specific T cell unresponsiveness in vitro and in vivo. J Exp Med. 1987 Feb 1;165(2):302–319. doi: 10.1084/jem.165.2.302. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Kamel-Reid S., Dick J. E. Engraftment of immune-deficient mice with human hematopoietic stem cells. Science. 1988 Dec 23;242(4886):1706–1709. doi: 10.1126/science.2904703. [DOI] [PubMed] [Google Scholar]
  12. Kang S. M., Beverly B., Tran A. C., Brorson K., Schwartz R. H., Lenardo M. J. Transactivation by AP-1 is a molecular target of T cell clonal anergy. Science. 1992 Aug 21;257(5073):1134–1138. doi: 10.1126/science.257.5073.1134. [DOI] [PubMed] [Google Scholar]
  13. LaSalle J. M., Tolentino P. J., Freeman G. J., Nadler L. M., Hafler D. A. Early signaling defects in human T cells anergized by T cell presentation of autoantigen. J Exp Med. 1992 Jul 1;176(1):177–186. doi: 10.1084/jem.176.1.177. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Lehmann P. V., Schumm G., Moon D., Hurtenbach U., Falcioni F., Muller S., Nagy Z. A. Acute lethal graft-versus-host reaction induced by major histocompatibility complex class II-reactive T helper cell clones. J Exp Med. 1990 May 1;171(5):1485–1496. doi: 10.1084/jem.171.5.1485. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. MacDonald H. R., Lees R. K., Baschieri S., Herrmann T., Lussow A. R. Peripheral T-cell reactivity to bacterial superantigens in vivo: the response/anergy paradox. Immunol Rev. 1993 Jun;133:105–117. doi: 10.1111/j.1600-065x.1993.tb01512.x. [DOI] [PubMed] [Google Scholar]
  16. McCune J. M., Namikawa R., Kaneshima H., Shultz L. D., Lieberman M., Weissman I. L. The SCID-hu mouse: murine model for the analysis of human hematolymphoid differentiation and function. Science. 1988 Sep 23;241(4873):1632–1639. doi: 10.1126/science.241.4873.1632. [DOI] [PubMed] [Google Scholar]
  17. Mosier D. E., Gulizia R. J., Baird S. M., Wilson D. B., Spector D. H., Spector S. A. Human immunodeficiency virus infection of human-PBL-SCID mice. Science. 1991 Feb 15;251(4995):791–794. doi: 10.1126/science.1990441. [DOI] [PubMed] [Google Scholar]
  18. Mosier D. E., Gulizia R. J., Baird S. M., Wilson D. B. Transfer of a functional human immune system to mice with severe combined immunodeficiency. Nature. 1988 Sep 15;335(6187):256–259. doi: 10.1038/335256a0. [DOI] [PubMed] [Google Scholar]
  19. Mueller D. L., Jenkins M. K., Schwartz R. H. Clonal expansion versus functional clonal inactivation: a costimulatory signalling pathway determines the outcome of T cell antigen receptor occupancy. Annu Rev Immunol. 1989;7:445–480. doi: 10.1146/annurev.iy.07.040189.002305. [DOI] [PubMed] [Google Scholar]
  20. Murphy W. J., Bennett M., Anver M. R., Baseler M., Longo D. L. Human-mouse lymphoid chimeras: host-vs.-graft and graft-vs.-host reactions. Eur J Immunol. 1992 Jun;22(6):1421–1427. doi: 10.1002/eji.1830220614. [DOI] [PubMed] [Google Scholar]
  21. Namikawa R., Weilbaecher K. N., Kaneshima H., Yee E. J., McCune J. M. Long-term human hematopoiesis in the SCID-hu mouse. J Exp Med. 1990 Oct 1;172(4):1055–1063. doi: 10.1084/jem.172.4.1055. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Norton S. D., Hovinen D. E., Jenkins M. K. IL-2 secretion and T cell clonal anergy are induced by distinct biochemical pathways. J Immunol. 1991 Feb 15;146(4):1125–1129. [PubMed] [Google Scholar]
  23. Rocha B., von Boehmer H. Peripheral selection of the T cell repertoire. Science. 1991 Mar 8;251(4998):1225–1228. doi: 10.1126/science.1900951. [DOI] [PubMed] [Google Scholar]
  24. Saxon A., Feldhaus J., Robins R. A. Single step separation of human T and B cells using AET treated srbc rosettes. J Immunol Methods. 1976;12(3-4):285–288. doi: 10.1016/0022-1759(76)90050-8. [DOI] [PubMed] [Google Scholar]
  25. Saxon A., Macy E., Denis K., Tary-Lehmann M., Witte O., Braun J. Limited B cell repertoire in severe combined immunodeficient mice engrafted with peripheral blood mononuclear cells derived from immunodeficient or normal humans. J Clin Invest. 1991 Feb;87(2):658–665. doi: 10.1172/JCI115043. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Sloan-Lancaster J., Evavold B. D., Allen P. M. Induction of T-cell anergy by altered T-cell-receptor ligand on live antigen-presenting cells. Nature. 1993 May 13;363(6425):156–159. doi: 10.1038/363156a0. [DOI] [PubMed] [Google Scholar]
  27. Sprent J., Schaefer M., Hurd M., Surh C. D., Ron Y. Mature murine B and T cells transferred to SCID mice can survive indefinitely and many maintain a virgin phenotype. J Exp Med. 1991 Sep 1;174(3):717–728. doi: 10.1084/jem.174.3.717. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Tary-Lehmann M., Rolink A. G., Lehmann P. V., Nagy Z. A., Hurtenbach U. Induction of graft versus host-associated immunodeficiency by CD4+ T cell clones. J Immunol. 1990 Oct 1;145(7):2092–2098. [PubMed] [Google Scholar]
  29. Tary-Lehmann M., Saxon A. Human mature T cells that are anergic in vivo prevail in SCID mice reconstituted with human peripheral blood. J Exp Med. 1992 Feb 1;175(2):503–516. doi: 10.1084/jem.175.2.503. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Torbett B. E., Picchio G., Mosier D. E. hu-PBL-SCID mice: a model for human immune function, AIDS, and lymphomagenesis. Immunol Rev. 1991 Dec;124:139–164. doi: 10.1111/j.1600-065x.1991.tb00620.x. [DOI] [PubMed] [Google Scholar]
  31. Trenn G., Sykora J., Michel M. C., Brittinger G. Functional and biochemical characterization of a calcium-ionophore-induced state of unresponsiveness in a cytolytic T cell clone. J Immunol. 1992 Mar 1;148(5):1338–1346. [PubMed] [Google Scholar]
  32. Webb S., Morris C., Sprent J. Extrathymic tolerance of mature T cells: clonal elimination as a consequence of immunity. Cell. 1990 Dec 21;63(6):1249–1256. doi: 10.1016/0092-8674(90)90420-j. [DOI] [PubMed] [Google Scholar]
  33. Williams S. S., Umemoto T., Kida H., Repasky E. A., Bankert R. B. Engraftment of human peripheral blood leukocytes into severe combined immunodeficient mice results in the long term and dynamic production of human xenoreactive antibodies. J Immunol. 1992 Oct 15;149(8):2830–2836. [PubMed] [Google Scholar]

Articles from The Journal of Experimental Medicine are provided here courtesy of The Rockefeller University Press

RESOURCES