Abstract
The inbred strain STS/A exhibits a higher proliferative response in the mixed lymphocyte culture (MLC) to stimulator cells of all 11 tested inbred mouse strains with 10 different major histocompatibility complex (MHC) haplotypes, as well as to stimulation with IL-2 than does the strain BALB/cHeA. However, alloantigen-stimulated BALB/c cells produce more IL-2 than STS/A cells. To study the genetic basis of these differences, we used 20 recombinant congenic strains (RCS) of the CcS/Dem series. Each of these CcS/Dem RC strains contains a different subset of about 12.5% of genes from the STS/A strain and the remaining approximately 87.5% of BALB/c origin genes. As a result the multiple non-linked genes responsible for phenotypic differences between BALB/c and STS/A became separated into different CcS/Dem strains. The strain distribution pattern (SDP) of high or low MLC response of individual CcS/Dem strains to stimulator cells of four different strains was almost identical, indicating that differences in responsiveness, rather than the alloantigenic difference itself, determine the magnitude of the response, and that the responsiveness to different alloantigens is largely controlled by the same genes. The SDP of IL-2 stimulation was different from that of MLC responsiveness. The differences in the proliferative responses observed among individual CcS/Dem strains were not due to differences in numbers of CD3+, CD4+ or CD8+ cells or to the observed differences in IL-2 production, and hence they likely reflect genetically determined intrinsic properties of T cells. These results show that a set of non-linked genes controls proliferative responses in MLC irrespective of the MHC haplotype of the stimulator cells, and that stimulation with IL-2 and production of IL-2 are controlled by different subsets of genes. Since the genomes of all RCS are extensively characterized by microsatellite markers, they can be used to map the genes controlling proliferative responsiveness to stimulation with alloantigens and IL-2.
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Bach, F. H. Transplantation: pairing of donor and recipient.Science 168: 1170–1179, 1970
Bejarano, M.-T., de Waal Malefyt, R., Abrams, J. S., Bigler, M., Bacchetta, R., de Vries, J. E., and Roncarolo, M.-G. Interleukin 10 inhibits allogeneic proliferative and cytotoxic T cell responses generated in primary mixed lymphocyte cultures.Inter Immunol 4: 1389–1397, 1992
Bucy, R. P., Hanto, D. W., Berens, E., and Schreiber, R. D. Lack of an obligate role of IFNγ in the primary in vitro mixed lymphocyte response.J Immunol 140: 1148–1152, 1988
Ceredig, R., Lowenthal, J. W., Nabholz, M., and MacDonald, H. R. Expression of interleukin-2 receptors as a differentiation marker on intrathymic stem cells.Nature 314: 98–100, 1985
Danzer, S. G., Kirchnier, H., and Rink, L. Cytokine interactions in human mixed lymphocyte culture.Transplantation 57: 1638–1642, 1994.
Demant, P. and Hart, A. A. M. Recombinant congenic strains—a new tool for analysis of genetic traits determined by more than one gene.Immunogenetics 24: 416–422, 1986
Dialynas, D. P., Wilde, D. B., Marrack, P., Pierres, A., Wall, K. A., Havran, W., Otten, G., Loken, M. R., Pierres, M., Kappler, J., and Fitch, F. W. Characterization of the murine antigenic determinant designated L3T4a, recognized by monoclonal antibody GK1.5: expression of L3T4 by functional T-cell clones appears to correlate primarily with class II MHC antigen-reactivity.Immunol Rev 74: 29–56, 1983.
Gillis, S., Ferm, M. M., Ou, W., and Smith, K. A. T-cell growth factor: parameters of production and a quantitative microassy for activity.J Immunol 120: 2027–2032, 1978
Gottlieb, P. D., Marshak-Rothstein, A., Auditore-Hargreaves, K., Berhoben, D. B., August, D. A., Posche, R. M., and Benedetto, J. D. Construction and properties of new Lyt-congenic strains and anti-Lyt-2.2 and anti-Lyt-3.1 monoclonal antibodies.Immunogenetics 10: 545–555, 1980
Groot, P. C., Moen, C. J. A., Dietrich, W., Stoye, J. P., Lander, E. S., and Demant, P. The recombinant congenic strains for analysis of multigenic traits: genetic composition.FASEB J 6: 2826–2835, 1992
Häyry, P., Andersson, L. C., Nordling, S., and Virolainen, M. Allograft response in vitro.Transpl Rev 12: 91–140, 1972.
Heremans, H., Dijkmans, R., Sobis, H., Van de Kerchhove, F., and Billiau, A. Regulation by interferons of the local inflammatory response to bacterial lipopolysaccharide.J Immunol 138: 4175–4179, 1987
Julius, M. H., Simpson, E., and Herzenberg, L. A. A rapid method for the isolation of functional thymus-derived murine lymphocytes.Eur J Immunol 3: 645–649, 1973
Lake, P., Clark, E. A., Khorshidi, M., and Sunshine, G. H. Production and characterization of cytotoxic Thy-1 antibody secreting hybrid cell lines.Eur J Immunol 9: 875–876, 1979
Leenaerts, P. L., Ceuppens, J. L., Van Damme, J., Michielsen, P., and Waer, M. Evidence that stimulator cell-derived IL-6 and IL-1 are released in the mixed lymphocyte culture but are not requisite for responder T cell proliferation.Transplantation 54: 1071–1078, 1992
Lipoldová, M., Kosařová, M., Zajícová, A., Holánň, V., Hart, A. A. M., Krulová, M., and Demant, P. Separation of multiple genes controlling the T-cell proliferative response to IL-2 and anti-CD3 using recombinant congenic strains.Immunogenetics 41: 301–311, 1995
Martinez, O. M., Villanueva, J. C., Lake, J., Roberts, J. P., Ascher, N. L., and Krams, S. M. IL-2 and IL-5 gene expression in response to alloantigens in liver allograft recipients and in vitro.Transplantation 55: 1159–1166, 1993
McKenzie, D. Alloantigen presentation by B cells: requirement for II-1 and IL-6.J Immunol 141: 2907–2911, 1988
Moen, C. J. A., van der Valk, M. A., Snoek, M., van Zutphen, L. F. M., von Deimpling, O., Hart, A. A. M., and Demant, P. The recombinant congenic strains: a novel genetic tool applied to the study of colon tumor development in the mouse.Mammalian Genome 1: 217–227, 1991
Moen, C. J. A., Snoek, M., Hart, A. A. M., and Demant, P. Scc-1, a novel colon cancer susceptibility gene in the mouse: linkage to CD44 (Ly-24, Pgp-1) on chromosome 2.Oncogene 7: 563–566, 1992.
Mori, N., Okumoto, M., van der Valk, M. A., Imai, S., Haga, S., Esaki, K., Hart, A. A. M., and Demant, P. Genetic dissection of susceptibility to radiation-induced apoptosis of thymocytes and mapping of Rapop1, a novel susceptibility gene.Genomics 25: 609–614, 1995a
Mori, N., Okumoto, M., Hart, A. A. M., and Demant, P. Apoptosis susceptibility genes mapped on mouse chromosome 9 (Rapop2) and chromosome 3 (Rapop3).Genomics 30: 553–557, 1995b
Mosmann, T. R., Cherwinski, H., Bond, M. W., Giedlin, M. A., and Coffman, R. L. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins.J Immunol 136: 2348–2357, 1986
Mosmann, T. R., Schumacher, J. H., Fiorentino, D. F., Leverah, J., Moore, K. W., and Bond, M. W. Isolation of monoclonal antibodies specific for IL-4, IL-5, IL-6 and a new Th2-specific cytokine (IL-10), cytokine synthesis inhibitory factor, by using a solid phase radioimmunoadsorbent assay.J Immunol 145: 2938–2945, 1990
Ohara, J. and Paul, W. E. Production of monoclonal antibody to and molecular characterization of B-cell stimulatory factor-1.Nature 315: 333–336, 1985
Paul, W. E. Pleiotropy and redundancy: T cell-derived lymphokines in the immune response.Cell 57: 521–524, 1989
Puré, E., Inaba, K., and Metlay, J. Lymphokine production by murine T cells in mixed leukocyte reaction.J Exp Med 168: 795–800, 1988
Rychlíková, M., Demant, P., and Ivanyi, P. The mixed lymphocyte reaction in H-2K, H-2D, and non-H-2 incompatibility.Biomedicine 18: 401–407, 1973
Snoek, M., van Vugt, H., and Groot, P. C. New microsatellite size variants as markers for a cross-over hotspot in theC4-H-2D region.Mammalian Genome 5: 174–176, 1994
Taniguchi, T. and Minami, Y. The IL-2/IL-2 receptor system. A current overview.Cell 73: 5–8, 1993.
Tomonari, K. A rat antibody against a structure functionally related to the mouse T-cell receptor/T3 complex.Immunogenetics 28: 455–458, 1988
Von Deimling, O. H., Forejt, J., and Wienker, T. F. Allelic profile at 37 biochemical loci of two inbred strains of the house mouse derived from wildMus musculus musculus.Labor Animals 22: 61–66, 1988.
Wysocki, L. J. and Sato, V.L., “Panning” for lymphocytes: a method for cell selection.Proc Natl Acad Sci USA 75: 2844–2848, 1978
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Holáň, V., Lipoldová, M. & Demant, P. Identical genetic control of MLC reactivity to different MHC incompatibilities, independent of production of and response to IL-2. Immunogenetics 44, 27–35 (1996). https://doi.org/10.1007/BF02602654
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DOI: https://doi.org/10.1007/BF02602654