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IB Region in the H-2 Complex Proc. Nati Acad. Sci. USA Vol. 78, No. 6, pp. 3809-3813, June 1981 Immunology A novel type of T-T cell interaction removes the requirement for I-B region in the H-2 complex (Ia antigens/Ir genes/T-cell proliferation/suppression) CONSTANTIN N. BAXEVANIS, ZOLTAN A. NAGY, AND JAN KLEIN* Max-Planck-Institut fir Biologie, Abteilung Immungenetik, 7400 Tuibingen, Federal Republic of Germany Communicated by George Klein, February 26, 1981 ABSTRACT When tested in the in vitro T-cell proliferation MATERIALS AND METHODS assay, H-2a cells are nonresponders to lactate dehydrogenase B (LDH-B; L-lactate:NAD' oxidoreductase, EC 1.1.1.27) and to IgG2a myeloma protein. However, the cells can be converted into Mice. Mice were obtained from our colony at the Max- responders either by the addition to the culture ofmonoclonal anti- Planck-Institute for Biology. The strains and their alleles at H- Ia.m7 antibody or by the removal from the culture of Lyt-2+ [T- 2 regions are given in Table 1. lymphocyte-associated alloantigen (Lyt)-2 positive] lymphocytes. Antigens. The ammonium sulphate precipitate of LDH-B4 In both instances, the responsiveness can be suppressed again by (Boehringer Mannheim) was extensively dialyzed against cul- the addition to the culture of monoclonal antibodies to I region- ture medium and stored at 4°C. Purified IgG2a myeloma pro- associated (Ia) molecules controlled by the I-A subregion. These teins UPC10 and RPC5 were obtained from Bionetics (Frank- data suggest that, in some H-2 haplotypes, the response to LDH- furt, Federal Republic of Germany) and stored at -70°C. B and IgG2a is the result of interaction between the I-A and I-E Antibodies. Hybridoma antibodies in ascites form were a gift subregions. The H-2l haplotype carries a responder allele at the from G. Hammerling (German Cancer Research Center, Hei- I-A subregion but the responsiveness ofH-2a cells is normally sup- delberg, Federal Republic of Germany). The following anti- pressed by T cells recognizing the antigen in the context of the I- bodies were used: B15-124R4 (anti-Ia.m2), 13/18 (anti-Ia.m7), E molecules. When the recognition ofI-E molecules is blocked by B22-277Rl9 (anti-Ia.m8), 17-227R7 (anti-Ia.m5, recognizing an antiserum or when the cells capable of this recognition are re- Ia. 15), B22-24aRl (anti-H-2.m2), and H100-30/3 (anti-H-2.m5) moved, the H-2' cells become responders. These experiments (11). Antibody P47-42 (anti-Ia. m9, recognizing Ia. 13) was a gift demonstrate a nonresponder turned responder by antibody in- hibition. They also demonstrate that the postulate ofthei-B subre- from G. Gotze (Max-Planck-Institute for Biology, Tfibingen, gion is no longer necessary and provide additional evidence that Federal Republic of Germany). Nonspecific inhibitory sub- the Ia molecules are the products of the immune response (Ir) stances of low molecular weight occasionally present in ascites genes. fluids were removed by ultrafiltration with Amicon XM-1OOA filters (12). Lyt-2.2 (K564 pool III) alloantiserum [againstT-lym- The specificity ofantigen recognition by T cells is restricted by phocyte-associated alloantigen (Lyt)-2.2] was produced by im- genes in the major histocompatibility complex (MHC) (1). Two munizing (B6-Ly-2a X C3H/HeJ)F1 mice with C57BL/6 thy- recent lines ofevidence indicate that the immune response (Ir)- mocytes and was tested for specificity as described (13). gene phenomenon, that is the MHC-controlled difference in Immunization and Cell Cultures. Mice were injected sub- immune responsiveness to certain antigens (reviewed in ref. 2), cutaneously at the base of the tail with 50 ,ug of LDH-B or is a manifestation of this restriction. First, Ir-gene products The stan- have been shown to be expressed on the antigen-presenting cell myeloma proteins in complete Freund's adjuvant (14). but not on the responding T cell, and they appear to function dard in vitro T-cell proliferation assay of Alkan (14) was used by providing the MHC context for recognition of the foreign with slight modifications as described (7). Antigen concentration antigen (3, 4). Second, with one exception, Ir loci ofthe MHC in the cultures was 15 ,ug/ml of LDH-B and 125 jig/ml ofmy- appear to be identical with those coding for plasma-membrane eloma protein. Control cultures contained concanavalin A I region-associated (Ia) molecules (5-8). The exception is the Ir (Wellcome, 25 yg per ml) or medium alone. Monoclonal anti- gene that maps in the so-called I-B subregion (here B region, bodies at the appropriate dilutions were included in the same for short) of the H-2 complex. The B region controls the re- volume (0.2 ml) of medium and were present throughout the sponse to at least two antigens, IgG2a myeloma protein (9) and culture period. Proliferation was measured by [3H]thymidine lactate dehydrogenase B (LDH-B; L-lactate:NAD' oxidoreduc- uptake on day 3 ofculture (7). All determinations were done in tase, EC 1. 1. 1.27) (10), but codes for no serologically detectable triplicate, and data were expressed as cpm ± SD. Significant membrane molecule. responses over background (i.e., cells without antigen) were In this communication we provide evidence that the B region calculated by using Student's t-test. The proliferation was me- is an illusion generated by a previously unrecognized form of diated by T cells as demonstrated by abrogation ofthe response interaction between two other regions ofthe H-2 complex, the after treatment of the lymph-node cells with Thy-1.2-specific A region and the E region. Thus, we remove the last objection antiserum and rabbit complement (data not shown). to the hypothesis in which the serologically detectable MHC molecules are the Ir-gene products. Abbreviations: Ia, I region-associated; Ir, immune response; LDH-B, lactate dehydrogenase B (L-lactate:NAD' oxidoreductase, EC 1.1.1.27); The publication costs ofthis article were defrayed in part by page charge Lyt, T-lymphocyte-associated alloantigen; MHC, major histocompati- payment. This article must therefore be hereby marked "advertise- bility complex. ment" in accordance with 18 U. S. C. §1734 solely to indicate this fact. * To whom reprint requests should be addressed. 3809 Downloaded by guest on October 2, 2021 3810 Immunology: Baxevanis et al. Proc. Natl. Acad. Sci. USA 78 (1981) Table 1. Proliferative T cell responses of standard and recombinant strains to LDH-B Alleles at H-2 regions Anti-LDH-B proliferative response H-2 Respondert Experiments, Strain haplotype K A B J E S D A cpm range* S.I. ranget status no. C57BL/6 b b b b b b b b 11,590-76,895 4.6-11.6 + 4 BO.D2 d d d d d d d d 20,042-70,502 4.7-16.5 + 3 B1O.GD g2 d d d b b b b 15,352-58,442 5.5-14.7 + 3 B1O.A a k k k k k d d -596-947 0.7-1.3 - 4 A.AL al k k k k k k d -1779-375 0.8-1.5 - 4 BlO.A(2R) h2 k k k k k d b -865-1,141 0.9-1.5 7 B1O.A(4R) h4 k k b b b b b 5,241-36,307 3.6-17.5 + 4 BlO.A(5R) i5 b b b k k d d 4,959-56,385 4.7-16.5 + 3 B1O.WB j j j j j j j j -162-587 0.9-1.2 - 4 BMO.P p p p p p p p p 3,566-32,160 6.2-25.2 + 3 B1O.Q q q q q q q q q 4,075-42,375 3.2-13.7 + 3 BlO.RIII r r r r r r r r 49,765 13.3 + 1 B1O.S s s s s s s s s 35,296 10.1 + 1 BlO.S(9R) t4 s 8 . k k d d 19,124 6.9 + 1 B1O.HTT t3 s s s s k k d 26,046-28,425 8.4-9.8 + 2 BlO.SM v v v v v v v v 60,000 11.7 + 1 * cpm of cultures with antigen-cpm of cultures without antigen, lowest and highest value, respectively. t Lowest and highest stimulation index (ratio of cpm in cultures with/without antigen). * Responder (+): significant proliferative responses in all experiments. Nonresponder (-): no significant response over background. § Putative alleles of recombinant strains used for definition of the I-B subregion are boxed. Treatment of Cells with Lyt-2.2-Specific Antiserum and Proliferative T-Cell Responses of Standard and Recombi- Complement. One volume ofcell suspension (1 x 107 cells per nant H-2 Haplotypes to LDH-B. The antibody response of the ml) was incubated with 1 vol of antiserum or normal mouse inbred mouse strains to LDH-B is controlled by a dominant Jr serum (1:5 dilution) at 4°C for 45 min. Thereafter, 1 vol ofrabbit gene that maps to the B region of the H-2 complex (10). We on vitro complement (1:4) was added, and incubation was continued at tested whether the same Ir-gene effect is exerted the in 37°C for 1 hr (13). proliferative response of T cells to LDH-B. The effect of antigen concentration on the proliferative re- RESULTS sponse ofprimed lymph-node cells is shown by the experiments Rationale. The original definition ofthe B region was based in Fig.
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