Skip to main content
NCBI home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1993 Jul 1;178(1):223–229. doi: 10.1084/jem.178.1.223

Hematopoietic cells and radioresistant host elements influence natural killer cell differentiation

PMCID: PMC2191072  PMID: 8315379

Abstract

Radioresistant host elements mediate positive selection of developing thymocytes, whereas bone marrow-derived cells induce clonal deletion of T cells with receptors that are strongly autoreactive. In contrast to T cell development, little is known about the elements governing the natural killer (NK) cell repertoire, which, similar to the T cell repertoire, differs between individuals bearing different major histocompatibility complex (MHC) phenotypes. We have used murine bone marrow transplantation models to analyze the influence of donor and host MHC on an NK cell subset. We examined the expression of Ly-49, which is strongly expressed on a subpopulation of NK cells of H-2b mice, but not by NK cells of H-2a mice, probably because of a negative effect induced by the interaction of Ly-49 with Dd. To evaluate the effect of hematopoietic cell H-2a expression on Ly-49 expression of H- 2b NK cells, we prepared mixed allogeneic chimeras by administering T cell-depleted allogeneic (B10.A, H-2a) and host-type (B10, H-2b) marrow to lethally irradiated B10 mice, or by administering B10. A marrow to B10 recipients conditioned by a nonmyeloablative regimen. Expression of H-2a on bone marrow-derived cells was sufficient to downregulate Ly-49 expression on both H-2a and H-2b NK cells. This downregulation was thymus independent. To examine the effect of H-2a expressed only on radioresistant host elements, we prepared fully allogeneic chimeras by administering B10 bone marrow to lethally irradiated B10.A recipients. B10 NK cells of these fully allogeneic chimeras also showed downregulation of Ly-49 expression. The lower level of H-2a expressed on H-2b x H-2a F1 cells induced more marked downregulation of Ly-49 expression on B10 NK cells when presented on donor marrow in mixed chimeras than when expressed only on radioresistant host cells. Our studies show that differentiation of NK cells is determined by interactions with MHC molecules expressed on bone marrow-derived cells and, to a lesser extent, by MHC antigens expressed on radioresistant host elements.

Full Text

The Full Text of this article is available as a PDF (707.0 KB).

Selected References

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

  1. Ballas Z. K., Rasmussen W. NK1.1+ thymocytes. Adult murine CD4-, CD8- thymocytes contain an NK1.1+, CD3+, CD5hi, CD44hi, TCR-V beta 8+ subset. J Immunol. 1990 Aug 15;145(4):1039–1045. [PubMed] [Google Scholar]
  2. Blazar B. R., Taylor P. A., Snover D. C., Bluestone J. A., Vallera D. A. Nonmitogenic anti-CD3F(ab')2 fragments inhibit lethal murine graft-versus-host disease induced across the major histocompatibility barrier. J Immunol. 1993 Jan 1;150(1):265–277. [PubMed] [Google Scholar]
  3. Ciccone E., Pende D., Viale O., Di Donato C., Tripodi G., Orengo A. M., Guardiola J., Moretta A., Moretta L. Evidence of a natural killer (NK) cell repertoire for (allo) antigen recognition: definition of five distinct NK-determined allospecificities in humans. J Exp Med. 1992 Mar 1;175(3):709–718. doi: 10.1084/jem.175.3.709. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Ciccone E., Pende D., Viale O., Than A., Di Donato C., Orengo A. M., Biassoni R., Verdiani S., Amoroso A., Moretta A. Involvement of HLA class I alleles in natural killer (NK) cell-specific functions: expression of HLA-Cw3 confers selective protection from lysis by alloreactive NK clones displaying a defined specificity (specificity 2). J Exp Med. 1992 Oct 1;176(4):963–971. doi: 10.1084/jem.176.4.963. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Gao E. K., Lo D., Sprent J. Strong T cell tolerance in parent----F1 bone marrow chimeras prepared with supralethal irradiation. Evidence for clonal deletion and anergy. J Exp Med. 1990 Apr 1;171(4):1101–1121. doi: 10.1084/jem.171.4.1101. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Höglund P., Ljunggren H. G., Ohlén C., Ahrlund-Richter L., Scangos G., Bieberich C., Jay G., Klein G., Kärre K. Natural resistance against lymphoma grafts conveyed by H-2Dd transgene to C57BL mice. J Exp Med. 1988 Oct 1;168(4):1469–1474. doi: 10.1084/jem.168.4.1469. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Höglund P., Ohlén C., Carbone E., Franksson L., Ljunggren H. G., Latour A., Koller B., Kärre K. Recognition of beta 2-microglobulin-negative (beta 2m-) T-cell blasts by natural killer cells from normal but not from beta 2m- mice: nonresponsiveness controlled by beta 2m- bone marrow in chimeric mice. Proc Natl Acad Sci U S A. 1991 Nov 15;88(22):10332–10336. doi: 10.1073/pnas.88.22.10332. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Ildstad S. T., Wren S. M., Bluestone J. A., Barbieri S. A., Sachs D. H. Characterization of mixed allogeneic chimeras. Immunocompetence, in vitro reactivity, and genetic specificity of tolerance. J Exp Med. 1985 Jul 1;162(1):231–244. doi: 10.1084/jem.162.1.231. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Koo G. C., Peppard J. R. Establishment of monoclonal anti-Nk-1.1 antibody. Hybridoma. 1984 Fall;3(3):301–303. doi: 10.1089/hyb.1984.3.301. [DOI] [PubMed] [Google Scholar]
  10. Kubo R. T., Born W., Kappler J. W., Marrack P., Pigeon M. Characterization of a monoclonal antibody which detects all murine alpha beta T cell receptors. J Immunol. 1989 Apr 15;142(8):2736–2742. [PubMed] [Google Scholar]
  11. MILLER J. F. Studies on mouse leukaemia. The role of the thymus in leukaemogenesis by cell-free leukaemic filtrates. Br J Cancer. 1960 Mar;14:93–98. doi: 10.1038/bjc.1960.11. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Marrack P., Lo D., Brinster R., Palmiter R., Burkly L., Flavell R. H., Kappler J. The effect of thymus environment on T cell development and tolerance. Cell. 1988 May 20;53(4):627–634. doi: 10.1016/0092-8674(88)90578-8. [DOI] [PubMed] [Google Scholar]
  13. Moretta L., Ciccone E., Moretta A., Höglund P., Ohlén C., Kärre K. Allorecognition by NK cells: nonself or no self? Immunol Today. 1992 Aug;13(8):300–306. doi: 10.1016/0167-5699(92)90042-6. [DOI] [PubMed] [Google Scholar]
  14. Ohlén C., Kling G., Höglund P., Hansson M., Scangos G., Bieberich C., Jay G., Kärre K. Prevention of allogeneic bone marrow graft rejection by H-2 transgene in donor mice. Science. 1989 Nov 3;246(4930):666–668. doi: 10.1126/science.2814488. [DOI] [PubMed] [Google Scholar]
  15. Ozato K., Henkart P., Jensen C., Sachs D. H. Spatially distinct allodeterminants of the H-2Kk molecule as detected by monoclonal anti-H-2 antibodies. J Immunol. 1981 May;126(5):1780–1785. [PubMed] [Google Scholar]
  16. Pollack S. B., Rosse C. The primary role of murine bone marrow in the production of natural killer cells. A cytokinetic study. J Immunol. 1987 Oct 1;139(7):2149–2156. [PubMed] [Google Scholar]
  17. Sharabi Y., Aksentijevich I., Sundt T. M., 3rd, Sachs D. H., Sykes M. Specific tolerance induction across a xenogeneic barrier: production of mixed rat/mouse lymphohematopoietic chimeras using a nonlethal preparative regimen. J Exp Med. 1990 Jul 1;172(1):195–202. doi: 10.1084/jem.172.1.195. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Sharabi Y., Sachs D. H. Mixed chimerism and permanent specific transplantation tolerance induced by a nonlethal preparative regimen. J Exp Med. 1989 Feb 1;169(2):493–502. doi: 10.1084/jem.169.2.493. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Sykes M., Chester C. H., Sundt T. M., Romick M. L., Hoyles K. A., Sachs D. H. Effects of T cell depletion in radiation bone marrow chimeras. III. Characterization of allogeneic bone marrow cell populations that increase allogeneic chimerism independently of graft-vs-host disease in mixed marrow recipients. J Immunol. 1989 Dec 1;143(11):3503–3511. [PubMed] [Google Scholar]
  20. Sykes M., Romick M. L., Sachs D. H. Interleukin 2 prevents graft-versus-host disease while preserving the graft-versus-leukemia effect of allogeneic T cells. Proc Natl Acad Sci U S A. 1990 Aug;87(15):5633–5637. doi: 10.1073/pnas.87.15.5633. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Sykes M., Sheard M., Sachs D. H. Effects of T cell depletion in radiation bone marrow chimeras. I. Evidence for a donor cell population which increases allogeneic chimerism but which lacks the potential to produce GVHD. J Immunol. 1988 Oct 1;141(7):2282–2288. [PubMed] [Google Scholar]
  22. Sykes M. Unusual T cell populations in adult murine bone marrow. Prevalence of CD3+CD4-CD8- and alpha beta TCR+NK1.1+ cells. J Immunol. 1990 Nov 15;145(10):3209–3215. [PubMed] [Google Scholar]
  23. Vukmanović S., Grandea A. G., 3rd, Faas S. J., Knowles B. B., Bevan M. J. Positive selection of T-lymphocytes induced by intrathymic injection of a thymic epithelial cell line. Nature. 1992 Oct 22;359(6397):729–732. doi: 10.1038/359729a0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Yankelevich B., Knobloch C., Nowicki M., Dennert G. A novel cell type responsible for marrow graft rejection in mice. T cells with NK phenotype cause acute rejection of marrow grafts. J Immunol. 1989 May 15;142(10):3423–3430. [PubMed] [Google Scholar]
  25. Yokoyama W. M., Jacobs L. B., Kanagawa O., Shevach E. M., Cohen D. I. A murine T lymphocyte antigen belongs to a supergene family of type II integral membrane proteins. J Immunol. 1989 Aug 15;143(4):1379–1386. [PubMed] [Google Scholar]
  26. Yokoyama W. M., Kehn P. J., Cohen D. I., Shevach E. M. Chromosomal location of the Ly-49 (A1, YE1/48) multigene family. Genetic association with the NK 1.1 antigen. J Immunol. 1990 Oct 1;145(7):2353–2358. [PubMed] [Google Scholar]
  27. Yokoyama W. M., Ryan J. C., Hunter J. J., Smith H. R., Stark M., Seaman W. E. cDNA cloning of mouse NKR-P1 and genetic linkage with LY-49. Identification of a natural killer cell gene complex on mouse chromosome 6. J Immunol. 1991 Nov 1;147(9):3229–3236. [PubMed] [Google Scholar]

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

RESOURCES