H-2I-linked control of immunological resistance to viral leukemogenesis as a response to preleukemic cells

The mechanism of resistance to leukemogenesis by two radiation leukemia virus variants, A-RadLV and D-RadLV, was investigated. Resistance to these viruses is linked toH-2I in both B10.S and C57BL/10 mice. The resistance of virus-infected mice to transplantation of syngeneic, A- or D-RadLV-induced lymphoma cells was similar to their resistance to leukemogenesis by the same viruses. This resistance could be transferred by lymphoid cells from immune donors to normal recipients, and it was specific for RadLV lymphomas. Virus-primed (responder x sensitive)F₁ hybrids rejected only resistant-type parental lymphoma cells. Hence, it appears thatH-2I-linked resistance to RadLV leukemogenesis is regulated byIr genes. Resistant mice immunized by A- or D-RadLV rejected syngeneic lymphoma cells, irrespective of whether they were sensitive or resistant to the RadLV variant used for the induction of the lymphoma cells. It follows that resistant and sensitive type lymphomas are antigenically similar for the effector mechanism, and that theIr genes may be expressed in the sensitization phase of the reaction. In virus-infected mice which are resistant to A- or D-RadLV we were able to demonstrate the presence of preleukemic lymphocytes. Normal mice could be immunized by these preleukemic cells against lymphoma challenge. These data are interpreted to suggest that mice havingH-2I-linked resistance to RadLV infection may be sensitized by their preleukemic cells, and that these preleukemic cells are then arrested in their development as a result of the immune response.     

A genetic analysis of natural resistance to nonsyngeneic cells: The role of H-2

The genetic control of natural resistance in vivo to four natural killer (NK) cell-resistant H-2 homozygous lymphoid tumor cell lines was investigated by following the survival and organ distribution of cells prelabeled with radioactive iododeoxyuridine. Backcross mice derived from DBA/2J and CBA/J parents were injected with H-2 ^dtumor cells and tumor cell elimination was lowest in H-2 ^dhomozygotes. Natural killer cell activity was also reduced in mice with the H-2 ^dhaplotype, but no direct correlation between NK cell levels against YAC-1 or SL2-5 lymphoma cells and natural resistance in vivo was demonstrable. Analysis of 23 BXD recombinant inbred strains indicated that natural resistance to H-2 ^dtumors was restricted to H-2 ^bstrains. There was no direct association of NK cell activity with H-2 type in the BXD strains and NK cell levels did not correlate with tumor survival in vivo. By comparing natural resistance to H-2 ^dand H-2 ^btumors in DBA/2, C57BL/6, B6D2F₁, and B10.D2 mice we found that H-2 nonidentity between the tumor and the host, rather than the host H-2 haplotype, determined whether natural resistance occurred. Again, NK cell activity against YAC-1 cells was not predictive of tumor survival in these strains. These results provide genetic evidence that NK cells alone cannot account for natural resistance to H-2 nonidentical cells of hemopoietic origin.     

Genetic control of “natural” killer lymphocytes in the mouse

Spleens from normal young mice contain lymphocytes that can kill certain in vitro grown Moloney lymphoma lines in a⁵¹Cr-release cytotoxicity test. A lymphoid cell without detectable T- or B-cell markers was previously shown to be responsible. Killing activity shows a marked dependence on the genotype of the donor mouse. When tested against a YAC line of strain A origin maintained in vitro spleens of A, A.CA, and A.SW mice had low activity, whereas CBA, C3H, C57L, and C57Bl spleens were highly active. In semisyngeneic F₁ crosses with strain A as one parent, reactivity resembled the opposite parental strain. Thus, (A×CBA)F₁, (A×C3H)F₁, (A×C57L)F₁, and (A×C57Bl)F₁ were reactive, whereas A×A.CA showed no significant activity. Analysis of the reactivity in (A×C57Bl)F₁×A backcross mice suggests that multiple genes are involved. Preliminary linkage analysis suggests at least oneH-2 linked factor. Another gene appears to be linked to theB (black) locus.     

Immune response deficiency of BSVS mice

The genetic control of the low response of BSVS mice to streptococcal Group A carbohydrate (GAC) was studied in crosses with responder A/J mice. F₁ mice were responders. In the backcross (BSVS × A/J)F₁ × BSVS mice, there were equal numbers of anti-GAC responder and nonresponder mice, indicating genetic control by a small number of major loci. The anti-GAC responses of the backcross mice showed no obligate linkage between responder status and A/JH-2 orIgC _H alleles. However, it was observed that the average anti-GAC titers were higher in backcross mice heterozygous at these loci. The above data, a lack of low-responder F₂ animals, and the segregation of a non-H-2-, non-IgC _H -linked locus in the first and second backcross mice, indicate that the defect in the BSVS anti-GAC responsiveness involves three loci: one linked toH-2, another linked toIgC _H , and a third locus —tentatively namedIr-GAC- not linked toH-2, IgC _H , orHbb.     

Natural resistance of irradiated 129-strain mice to bone marrow allografts: Genetic control by theH-2K region

A major genetic determinant of natural resistance to bone marrow allografts, designated asHh-3, was mapped to theH-2K region. This gene may code for or regulate the expression of cell surface structures selectively expressed on donor hemopoietic cells and recognized by naturally occurring cytotoxic effectors. Resistance was observed as failure of donor cell growth in the spleen of irradiated 129-strain (H-2 ^bc ) recipients of H-2^k bone marrow cells. The mapping was accomplished by substituting donor cells bearingk alleles throughout theH-2 complex with cells of recombinant mouse lines bearingk alleles at definedH-2 regions. The host antigraft reaction underlying resistance was abrogated by pretreating 129-strain mice with either rabbit antimouse lymphocyte serum or the antimacrophage agent silica. Grafting of H-2K^k cells into mice ancestrally unrelated to 129 but sharing theH-2 ^bc or the similarH-2 ^b haplotype, and intoH-2 ^b/k ,H-2 ^k/bc , andH-2 ^k/d F₁ hybrids revealed that resistance was unique to 129 mice, since mice of the other strains, including F₁ hybrids, were susceptible to the grafts. Thus,Hh-3 incompatibility was a necessary but insufficient condition for the manifestation of allogeneic resistance; other genetic factors not associated withH-2 conferred responder status to 129-strain mice and nonresponder status to D1.LP, B10.129(6M), B10, B6, and possibly to F₁ hybrid mice. The possible relationships between allogeneic resistance to H-2^k marrow grafts, hybrid resistance to H-2^k lymphomas, and F₁ hybrid antiparental H-2^k cytotoxicity induced in vitro are discussed.     

H-2-associated control of natural cytotoxicity and hybrid resistance against RBL-5

(C57B1 × DBA)F₁ hybrids were more resistant to the inoculation of 10³ Rauscher virus-induced, serially propagated RBL-5 cells than syngeneic C57Bl recipients. Resistance was linked toH-2^di in the C57Bl backcross. Spleen cells from nonimmune (C57Bl × DBA)F₁ hybrids were significantly more reactive against RBL-5 in the natural killer (NK) cytotoxicity test in vitro than were C57Bl spleen cells. In the C57Bl backcross,H-2^dH 2^b heterozygotes were more cytotoxic than theH- 2^B homozygotes. Along with RBL-5, they were also more cytotoxic to the Moloney virus-induced YAC lymphoma (of strain A origin) and to the human ALL-derived MOLT-4 line.     

Expression of the H-Y Antigen on thymus cells and skin: Differential genetic control linked toK end ofH-2

The strength of the H-Y antigen on thymus cells and on skin was compared in differentH-2-congenic mouse strains using a host-versus-graft reaction popliteal lymph node assay, and skin grafts from males of parental strains grafted to F₁ hybrid females. The results revealed considerable differences in the strength of the H-Y antigen among different congenic strains; these differences demonstrate the effect of theH-2-linked gene on the expression of the H-Y antigen. The linkage withH-2 was also confirmed in tests with segregating F₂ generations. In the strains bearing recombinantH-2 haplotypes, the strength of the H-Y antigen is similar to that of parental strain from which the recombinant received itsK end, and the responsible gene (or genes) map to the left ofI-C. The effect of theH-2-linked gene(s) on thymus cells and skin is different. The gene linked to theK end ofH- 2^b determines a strong H-Y antigen on thymus cells, but a relatively weak H-Y antigen on skin. The gene linked to theK end ofH- 2^k determines a weak H-Y antigen on thymus cells, but a strong H-Y antigen on skin. The gene linked to theK end ofH- 2^d determines a weak H-Y antigen on both thymus cells and skin. Our observations raise the possibility that the structural gene for the H-Y antigen is linked toH-2. Alternative (but not exclusive) explanations invoke regulatory effects ofH-2 on the expression of the H-Y antigen, possibly by means of the control of the cellular andogen receptors.     

Genetic control of two independently segregating loci in mice to the sequential polypeptide (Tyr-Ala-Glu-Gly)n

Immune responses to the sequential helical polypeptide (Tyr-Ala-Glu-Gly)_n [(T-A-G-Gly)_n] in mice is under the control of at least two separate genes. One gene,Ir-(T-A-G-Gly)-1, which is linked, toH-2 haplotypesb, f, andr, controls the ability to respond and maps to theIA subregion. A non-H-2-linked locus,Ir-(T-A-G-Gly)-2. is responsible for the magnitude of the antibody response, which is expressed as a high, intermediate, or low level of antibody production. The antibody produced is of the IgG class, and does not crossreact even with the closely related sequential helical polymer (Tyr-Glu-Ala-Gly)_n [(T-G-A-Gly)_n]. Immune responsiveness is a dominant trait,i.e., the F₁ generations of responder x nonresponder crosses are responders. However, the data obtained with both backcross populations are not easily interpretable. The contribution of the B-cell mitogenic activity of the sequential polymer to activation of suppressor T cells is considered as a possible explanation for the backcross results. The possible role of the Ia. W29 specificity present in the mouse strains responding to both (T-A-G-Gly)_n and calf skin collagen type I in modulating responses to the polymers is discussed.     

Sex-dependent effects of non-H-2 loci on lethal GVH reaction induced across an H-2 barrier

We have studied the influence of DBA/2 non-H-2 antigens on the lethal graft-versus-host reaction (GVHR) developed across an H-2 barrier. (DBA/2 x B10.D2)F₁ x B10.D2 (H-2 ^d) backcross (BC) mice were typed for their allelic constitution at nine genetically independent chromosome markers and used as individual cell donors simultaneously for two to three (DBA/2 X B10.D2)F₁ recipients incompatible for DBA/2 non-H-2 antigens alone and two to three (DBA/2 x B10.BR)F₁ recipients incompatible for DBA/2 non-H-2 antigens and H-2^k. The results showed that, when compared with that developed in a control group incompatible for H-2 ^kalone [B10.D2(B10.D2xB10.BR)F₁], the GVHR mortality seen in the presence of an additional incompatibility for DBA/2 non-H-2 antigens [(DBA/2 X B10.BR)F₁recipients] is significantly delayed but only in female mice. An analysis of individual BC donors indicated that this protective effect of DBA/2 non-H-2 antigens correlates with incompatibility for gene(s) linked to the Pgm-1 chromosome marker. In contrast, incompatibility for gene(s) linked to Mod-1 and Es-3 markers accelerates GVHR mortality, but only in male mice. Finally, the results obtained with (DBA/2 x B10.D2)F₁ and (DBA/2 x B10.BR)F₁ recipients were compared; they showed that the intensity of the GVHR developed by cells from individual BC donors against a given set of DBA/2 non-H-2 antigens correlates well with that developed by the same BC donor against the same set of non-H-2 antigens plus H-2^k. We conclude that certain non-H-2 genes (and antigens) can modulate the intensity of the GVHR developed across an H-2 barrier. The number of such genes is probably great; their effects are strong and complex, and can be sex-dependent.     

Positive selection of Tcrb-V10b+ T cells

The Tcrb-V10b⁺ T cell population has been examined with a newly established antibody, KT10b, specific for Tcrb-V10b but not Tcrb-V10a. H-2E⁺ mice have higher levels of Tcrb-V10b⁺ T cells (4.3%–11.%) than H-2E^– mice (2.2%–4.9%). This difference appears to be determined by levels of Tcrb-V10b⁺ T cells in the CD4 population. F₁ mice between H-2E⁺ and H-2E^– mice dominantly express higher levels of Tcrb-V10b⁺ T cells. [NOD (E–) x (NOD x A (E⁺))F₁] backcross mice show positive selection of Tcrb-V10b⁺ CD4⁺ T cells by H-2E. On the other hand other backcross analyses reveal positive selection of Tcrb-V10b⁺ CD8⁺ T cells by certain major histocompatibility class I molecules. Involvement of non-H-2 antigens in these positive selections remain to be determined. Address correspondence and offprint requests to: K. Tomonari.     

Experimental allergic orchitis in mice

Inbred strains of mice were studied for their susceptibility to the induction of experimental allergic orchitis after sensitization with mouse testicular homogenate in complete Freund's adjuvant accompanied by injections of extract from Bordetella pertussis. Susceptibility to autoimmune orchitis was found to be linked to the major histocompatibility complex in BALB/c and C57BL/10 mice and mapped to genes encoded within the H-2D ^dregion. In five of six groups of bidirectional (susceptible × resistant) F₁ hybrids, H-2D ^d-linked susceptibility was inherited as a dominant autosomal trait. However, in (BALB/cByJ × DBA/2J)F₁ and (DBA/2J × BALB/cByJ)F₁ hybrids, dominant autosomal resistance to the induction of autoimmune orchitis was observed. Backcross analysis between the resistant F₁ hybrid and the susceptible BALB/cByJ parent suggests that a single independently segregating DBA/2J locus is capable of negating H-2D ^d-linked susceptibility, and controls resistance to the induction of autoimmune orchitis.Abbreviations used in this paper BP extract Bordetella pertussis extract - CFA complete Freund's adjuvant - EAO experimental allergic orchitis - Ir immune response - MHC major histocompatibility complex - MLH mouse liver homogenate - MTH mouse testis homogenate - PI pathology index     

Teratocarcinoma transplantation rejection loci: AnH-2-linked tumor rejection locus

Embryoid bodies (ascites tumor) from a 129/Sv transplantable teratocarcinoma produce tumors (100%) in syngenic 129/Sv mice but fail to form tumors (3–6%) in BALB/c mice, C3H/He mice and C57BL/6 mice, in spite of the fact that the malignant stem cells of this tumor do not express detectable H-2 antigens. The available evidence indicates that this allogeneic tumor restriction has an immunological basis; 100% of the F₁ hybrid mice between 129/Sv and the three other inbred mouse strains accept the 129/Sv teratocarcinoma. The backcross and F₂ mice segregate the BALB/c, C3H/He and C57BL/6 tumor transplantation rejection loci in a manner that indicates that each of these inbred strains of mice contain one to two major transplantation rejection loci. A linkage analysis in the BALB/c and C3H/He backcross and F₂ generations indicates that these mice have a teratocarcinoma transplantation rejection locus on chromosome 17, about eight to nine recombination units from theH- 2 complex. An F₁ complementation analysis between allogeneic mice that each reject teratocarcinomas tumors (BALB/c × C57BL/6 and C3H/He × C57BL/6), indicates that the C57BL/6 mice have the 129/Sv tumor-accepting (sensitive) allele at theH-2-linked locus but reject teratocarcinomas because of antigenic differences at a second locus.While these major teratocarcinoma transplantation rejection loci determine the acceptance or rejection of a tumor by a mouse injected with high doses of tumor tissue (750 g of tumor protein), evidence is presented for a number of minor genetic factors that can (1) affect the efficiency of tumor rejection and (2) cause complete tumor rejection at lower tumor doses (7.5–75 g of tumor protein).     

Development of a ploidy series from a single interspecific Trifolium repens L.Ā . nigrescens Viv. F1 hybrid

 The objective of the current research was to generate a ploidy series of backcross progenies from a single triploid (2n=3x=24) Trifolium repens×T. nigrescens F₁ hybrid (3x H-6909-5). The 3x H-6909-5 plant was highly sterile and produced no seeds from approximately 3000 reciprocal backcrosses to both parental species. Chromosome doubling by an in vitro colchicine method resulted in a marked increase in fertility. Pollen stainability was increased from 9.9% in 3x H-6909-5 to an average of 89.2% (range 87.7–90.9%) in the three chromosome-doubled 6x H-6909-5 plants. Subsequent backcrosses of 6x H-6909-5 and interbreeding of backcross derivatives resulted in an array of fertile hybrids at 4x, 5x and 7x levels and some aneuploids. The occurrence of 7x BC₁F₁ progeny from the T. repens×6x H-6909-5 (4x×6x) cross is the first unequivocal evidence of functional female 2n gametes in white clover. Meiotic pairing in F₁ and BC₁F₁ progeny indicated the presence of allosyndetic pairing, suggesting that genetic exchange between the two species is possible. Received: 17 October 1996 / Accepted: 8 November 1996     

Susceptibility to a mouse acquired immunodeficiency syndrome is influenced by theH-2

The development of a mouse acquired immunodeficiency syndrome (MAIDS) induced following LP-BM5 MuLV infection depends on host genetic factors. Susceptible mice, such as C57BL/6J mice, develop a profound impairment of lymphoproliferative response to mitogens and hyperplasia of lymphoid organs and succumb to infection within 6 months. These changes do not occur in resistant mice, such as A/J mice. Resistance to MAIDS is a dominant trait since (C57BL/6JxA/J)F₁ hybrid mice did not develop any immune dysfunctions following infection. Genetic regulation of the trait of resistance/susceptibility to MAIDS was determined in AXB/BXA recombinant inbred (RI) mouse strains (derived from resistant A/J and susceptible C57BL/6J progenitors). Two different criteria were used to determine their resistance or susceptibility to developing MAIDS: the gross pathologic evaluation of lymphoid organs at 13–15 weeks of infection, and survival. RI mouse strains segregated into two non-overlapping groups. The first group did not develop any significant pathology, and these mouse strains were considered as resistant to MAIDS. The second group showed the virus-induced pathological changes as well as an immunological dysfunction as seen in C57BL/6J progenitor mice, and these strains were thus considered as susceptible to MAIDS. This bimodal strain distribution pattern of resistance/susceptibility to MAIDS among the RI strains suggests that this phenotype is controlled by a single gene. Linkage analysis with other allelic markers showed a strong association between resistance/susceptibility to MAIDS and theH-2 complex. Possession of theH-2 ^b haplotype derived from C57BL/6J mice was associated with susceptibility to MAIDS, while theH-2 ^a haplotype conferred resistance to the disease. This finding was confirmed by demonstrating thatH-2 ^a congenics on the susceptible C57BL/10 background were as resistant to MAIDS as A/J mice which donated theH-2 ^a locus. Gene(s) within theH-2 complex thus represent the major regulatory mechanism of resistance/susceptibility to MAIDS.     

A locus controlling the activity of UDP-galactose:GM2(NeuGc) galactosyltransferase in mouse liver is linked to the H-2 complex

Genetic polymorphism in the expression of the G_M1(NeuGc) ganglioside has been shown in the liver of inbred strains of mice. Through analysis of the gangliosides of H-2 congenic and recombinant strains, this polymorphism was demonstrated to be controlled by a locus mapped left outside of the H-2 complex on chromosome 17, and the locus was assumed to control the level of the activity of G_M1(NeuGc) synthetase, UDP-galactose:G_M2(NeuGc) galactosyltransferase (E.C.2.4.1.62) [Hashimotoet al., J Biochem (1983) 94:2049-54].In the present study we analyzed the genetic linkage between the activity of the galactosyltransferase and the H-2 haplotype. For this purpose, we selected two inbred strains of mice, WHT/Ht and BALB/c, because they have different levels of the transferase activity and show different H-2 haplotypes; the specific activity of the transferase obtained with BALB/c was one-eighth of that with WHT/Ht, and BALB/c expressed the la.7 antigen as one of the products encoded in their H-2^d complex, whereas WHT/Ht did not. To analyze the linkage between these two phenotypes, WHT/Ht were mated with BALB/c to obtain the F₁ mice, and the female F₁ mice were then backcrossed to WHT/Ht. It was found that one half of the backcross generation expressed the la.7 antigen derived from BALB/c and had a significantly lower specific activity of the transferase than that of WHT/Ht, while the other half did not express the la.7 antigen but had the same specific activity of the transferase as that obtained with WHT/Ht.These results suggest that the locus controlling the level of the transferase activity in mouse liver is linked to the H-2 complex on chromosome 17.Abbreviations NeuGc N-glycolylneuraminic acid The ganglioside nomenclature is based on the system of Svennerholm, J Neurochem (1963) 10:613-23. The sialic acid species present is shown in parentheses after the ganglioside abbreviation.     

Spontaneous loss and subsequent stimulation ofH-2 expression in clones of a heterozygous lymphoma cell line

The expression of H-2K^k antigens in a (C3H × DBA/2)F₁ lymphoma cell line growing in vitro was investigated with monoclonal antibodies specific for a public antigen of theH-2K ^k region (H-2.m3) in fluorescence analysis and microcytotoxicity assays and in cell-mediated cytotoxicity with allogeneically stimulated effector cells. Estimates of relative levels of H-2K^k-antigen expression obtained by the different methods were highly correlated. The uncloned, unselected population gradually lost H-2K^k surface antigen expression under culture conditions. This was due to the appearance of H-2K^k negative variants. Fifteen cloned sublines of a population enriched for cells expressing antigen H-2.m3 in the fluorescence activated cell sorter contained either two distinct populations, one consisting of H-2.m3 negative and one of H-2.m3 positive cells, or consisted of H-2.m3 negative cells only. The expression of the H-2.m3 determinant of H-2K^k paralleled that of other serological H-2K^k determinants and of H-2K^k target determinants for cell-mediated cytotoxicity. In nearly all clones where two populations could be detected, the proportion of H-2.m3 negative cells increased with time in culture. The amounts of H-2K^k antigen expressed by the clones appeared not to be correlated to the amounts of H-2D^k antigens on the cell surface as judged by cell-mediated cytotoxicity.In at least one clone and in the uncloned population, H-2K^k-antigen expression detectable by fluorescence analysis could be stimulated by growing the cells in the peritoneal cavities of (C3H × DBA/2)F₁ mice or by adding mouse interferon preparations to the cell cultures. The increase in susceptibility to cell-mediated lympholysis of cells grown in vivo paralleled the increase inH-2 expression detected by fluorescence. In contrast, cells growing in the presence of interferon in vitro showed reduced sensitivity to lysis by alloreactive lymphocytes, although H-2 antigens were strongly expressed as measured by fluorescence.     

Genetic control of the target structures recognized in hybrid resistance

Hybrid resistance of lethally irradiated (C57BL/6 × DBA/2)F₁ and (C57BL/10 × C3H)F₁ hybrid mice to the engraftment of parental C57BL/6 or C57BL/10 bone marrow cells is controlled by the H-2-linked Hh-1 locus. This resistance can be specifically blocked or inhibited by the injection of irradiated spleen cells from lethally irradiated, marrow reconstituted donor mice of certain strains. By testing the ability of regenerating spleen cells from various donor strains to block the resistance, we studied the genetic requirements for the expression of putative cell-surface structures recognized in hybrid resistance to H-2^b marrow cells. Strains of mice bearing informative intra-H-2 or H-2/ Qa-Tla recombinant haplotypes provided evidence that the Hh-1 locus is located telomeric to the H-2S region complement loci and centromeric to the H-2D region class I locus in the H-2 ^b chromosome. Two mutations that affect the class I H-2D ^b gene have no effect on Hh-1 ^b gene expression. The H-2D region of the H-2 ^S haplotype contains an allele of the Hh-1 locus indistinguishable from that of the H-2D ^b region, as judged by the phenotypes of relevant strains and F₁ hybrids. Collectively these data indicate that the Hh-1 locus is distinct from the class I H-2D (L) locus in the H-2 ^b or H-2 ^s genome, and favor the view that the expression or recognition of the relevant determinants is not associated with class I gene products.Abbreviations used in this paper BM(C) bone marrow (cells) - CML cell-mediated lympholysis - CTL cytotoxic T lymphocytes - FBS fetal bovine serum - HBSS Hanks' balanced salt solution - SC spleen cells from irradiated, bone marrow-reconstituted mice Address correspondence to: Dr. I. Najamura, Department of Pathology, School of Medicine, State University of New York at Buffalo, Buffalo, NY 14214, USA     

Complementation between a gene of theI-E subregion and a non-H-2 gene in the class-specific suppression of IgG2a antibody to sheep erythrocytes

A low level of IgG2a antibodies is observed in B10 mice after primary immunization with SRBC. Analysis of the response in different H-2^b mice and among B10 animals with differentH-2 haplotypes reveals that this selective isotype deficiency is under the control of at least two genes: a background gene and anH-2-linked gene. Responses ofH-2 recombinant B10 strains map theH-2-linked gene to theI-E subregion. Evidence is presented for complementation betweenH-2 and non-H-2 genes in the determination of the low responder phenotype. Low responsiveness appears to be inherited as a dominant trait. Possible functions of the two series of genes are discussed in relation to suppressor mechanisms.     

Differential effect of hybrid resistance on the localization of virus-immune effector T cells to spleen and brain

The hybrid resistance (Hr) effect operates in the lymphocytic choriomeningitis (LCM) in vivo transfer model to inhibit both the level of cytotoxicity T lymphocyte (CTL) generation in spleen and the induction of inflammation in cerebrospinal fluid (CSF). The effect is seen when LCM virus-immune T cells that are homozygous for H-2D ^b are injected into virus-infected, immunosuppressed recipients that are heterozygous for this allele, or into radiation chimeras that express an appropriate F₁ phenotype. Evidence that Hr to T -cell transfer is cell-dose-dependent and tends to diminish with age was found in both chimeric and normal F₁ mice. Inhibition of the capacity of injected T cells to cause meningitis is a more sensitive measure of Hr than is the further stimulation of CTL effectors in recipient lymphoid tissue. The injection of large numbers of H-2^b virus-immune T cells into (H-2 ^k X H-2 ^bF₁H-2 ^k) virus-infected recipients did not induce any cellular extravasation into CSF, though potent H-2^b-restricted CTL effectors were generated in recipient spleen. Evidence of minimal inflammatory process was found in one experiment where these chimeras were given a comparable dose of (H-2 ^b X H-2 ^d)F₁ immune spleen cells. Development of this Tcell-mediated immunopathological process depends essentially on the expression of the appropriate H-2 restriction element on radiation-resistant host cells which, in this case, presumably constitute part of the physiological barrier between blood and CSF.     

Xid-defective male (CBA/N x C57BL/6)F1 accessory cells present bovine insulin to long-term cultured F1-restricted T-cells

The reactivity of H-2^b-restricted murine T cells towards bovine insulin was reported to depend on the expression of Ia.W39, a private specificity of I-A^b, on antigen-presenting cells. Cells of male (CBA/N x B6)F₁ mice carrying the mutation xid on the X chromosome lack Ia.W39 on the cell surface. These cells are unable to present bovine insulin to primed T cells derived from female (CBA/N x B6)F₁ mice. We show here that spleen cells of male (CBA/N x B6)F₁ hybrids served perfectly as accessory cells for the insulin-dependent induction of a proliferative response of long-term cultured T cells with (B10 x B10.BR)F₁ genotype, restricted to recognizing insulin in the context of F₁-unique I-A determinants. The epitope on the insulin molecule essential for stimulation was determined to depend on the glutamic acid residue in position 4 of the A chain of insulin. This contrasts with the H-2^b-restricted response of B6 mice to bovine insulin, which appears to be directed at the A chain loop determinant (amino acids A8 and A10). These data suggest that distinct I-A^b-encoded structures, the expression of which is regulated independently, may serve as components of restriction elements for H-2^b and (H-2^b x H-2^k)F₁ restricted T cells, which are specific for different epitopes of bovine insulin.