Residual Minor Histocompatibility Genes Contaminate the B10. AM Congenic Line: No Evidence of C-Region-Controlled Histoincompatibility

After being primed in vivo and restimulated in vitro, cytolytic T lymphocytes (CTL) were produced in the strain combinations B10.AM ami-B10.A(1R) and B10.A(1R) anti-B10.AM. Although the two strains differ in the chromosomal interval between the E_α and the D loci, the CTL are not directed against antigens controlled by loci in this interval. Instead, the CTL detect minor histocompatibility (H) antigens controlled by loci that are notlinked to H-2 . The recognition of the antigens detected by the B10. AM anti-B10.A(lR) CTL is restricted by the K^k and D^b molecules, but the CTL also cross-react with the D^d molecule (or a molecule controlled by a locus closely linked to D^d). The recognition of the antigens detected by these two CTL behave as if controlled by alleles at the same minor H locus or loci. This locus is distinct from H-2 , and the B 10. AM congenic line apparently retained a C3H-derived allele at this locus.     

Rabbit Antisera with Specificity for Isolated Mouse T-Lymphocyte Receptors

Rabbit antibodies obtained after Immunization of mouse Immunoglobulin (Mig)-tolerant rabbits with B6 anti-CBA IgG and having specificity for B6 anti-CBA IgG and T-cell receptors (antiserum 5936) were used to isolate 5936-reactive molecules from B6 anti-CBA mixed lymphocyte culture supernatants. Such 5936-reactive molecules were produced by the B6 T cells, and they did not react with rabbit anti-MIg antisera. They had a mol. wt of 50,000–75,000, and were single-chain polypeptides that did not react with concanavalin A (Con A) Sepharose. These molecules were in turn injected into rabbits, and the antisera thus obtained had the following characteristics: (1) they reacted against B6 anti-CBA T-cell receptor material but not against B6 anti-CBA IgG; (2) they reacted with about 35% of B6 (H-2^b. Ig-1^b) anti-CBA T cells, 25% of B6 Con A blasts and 0 10%; of normal B6 T cells but not with B6 lipopolysaccharide (LPS) blasts, C3H.B10 (H-2^b, Ig-I) anti CBA or CBA anti-B6 T cells, CBA Con A blasts or normal CBA T cells: and (3) they reacted with the same 50,000–75.000 mol. wt, T-cell-derived molecules as did antiserum 5936. The implications of these findings are discussed in relation to the nature of T-cell receptors.     

Non-Diabetogenic Insulitis in NOD↔BIO. GD Allophenic Mice in Spite of Permissive Class I MHC Antigens

Allophenic mice (embryo aggregation mouse chimeras) enable us to dissect the process of spontaneous autoimmunity under physiological conditions. Our previous experiments showed that the autoimmune process in allophenic mice of the NOD↔C57Bl/6 strain combination does not progress from insulitis to diabetes. One possible explanation for this protection is that H-2 K^d-restricted CD8⁺ T cells kill only NOD ß cells (K^d, D^b) in the chimeric islets, while the B6ß cells (K^b, D^b) are spared from destruction. To test this hypothesis we analysed 22 NOD↔B10. GD chimeras in which the class I MHC are shared by both parental strains. Therefore all the ß cells in these chimeras express H-2 K^d molecules. Ten allophenic mice were killed at 7 weeks and studied for early pathology. No evidence for intra-islet infiltration was obtained at this age, suggesting that the autoimmune process in NOD↔B10. GD chimeras is slower than in NOD mice. Twelve chimeras were followed up for 1 year for disease development and all failed to progress to full-blown diabetes, despite the occurrence of intra-insulitis in six out of 12 mice. The lack of disease in NOD↔B10. GD chimeras demonstrates that class I MHC chimerism does not account for diabetes resistance in NOD-allophenic mice.     

Impact of MHC Class I Gene on Resistance to Murine AIDS

Development of murine AIDS in mice following infection with LP-BM5 murine leukaemia virus (MuLV) is highly strain dependent, with strain differences determind by genes within and outside H-2. Among H-2 genes, the D^d gene is the most closely associated with resistance to LP-BM5 MuLV infection. However, the D^d-mediated resistance is highly influenced by outside H-2 genes, i. e. A lineage strains are more resistant than mice strains of B6/B10 lineage. In this study, the mice having BALB background were analysed and, similarly to A lineage mice, only D^d gene products were found to be required to provide resistance to LP-BM5 MuLV infection. Furthermore, BALB/c Kh mice bearing both D^d and L^d genes clearly showed obviously higher resistance than BALB/c-H-2^dm2 mice solely having the D^d gene. In addition, in the long-term observation of the effect of the D^d gene on B6/B10 background mice, D8 mice having the D^d gene as a transgene and expressing a high level D^d gene product showed higher resistance than naturally recombinant B10. A(18R) mice. These results suggest that the MAIDS resistance associated with the D end loci is dependent on the level of expression of an MHC class I gene.     

Molecular specificity of a monoclonal anti-Ik alloantibody identifying a highly conserved determinant on mouse I-A, I-E and human DR antigens

We have investigated, using serological and biochemical assays, the specificity of an A.TH anti-A.TL-derived monoclonal antibody (mAb), designated 40.B, directed at a highly conserved antigenic determinant expressed on the majority of murine and human MHC class II antigens. In the mouse, mAb 40.B defines a new specificity expressed on the Ia products of the H-2 haplotypes k, d, b, v, r, p, u, j and w3. Analysis of its reactivity with H-2 recombinant strains and the results of the competitive binding inhibition of ¹²⁵I-labeled mAb 40.B to B10.BR cells with I-A^k and I-E^k specific mAb suggested recognition of a shared Ia determinant expressed on both I-A^k and I-E^k molecules. This has been confirmed by sequential immunoprecipitation studies which demonstrated the specificity of mAb 40.B for the A_β^k A_α^k, A_β^b A_α^b, A_β^d A_α^d, E_β^k E_α^k, E_β^s E_β^k, and E_β^d E_α^d dimers. In humans, this mAb bound to and immunoprecipitated HLA-D/DR molecules expressed on lymphoblastoid cell lines carrying the MTl and MT2 supertypic specificities. The possible implications of these findings with regard to an evolutionary model of MHC class II antigens are discussed.     

Peptide Binding to MHC Class I is Determined by Individual Pockets in the Binding Groove

H-2K^b and HLA-A2 are MHC⁴ class I molecules with a similar overall structure. Important differences between these two class I molecules reside in the structure of the individual pockets in the antigenic-peptide-binding groove. H-2K^b, which has a deep C pocket, binds specifically peptides with a tyrosine or a phenylalanine at position 5. In contrast, HLA-A2 has a shallow C pocket, which cannot accommodate large side chains at position 5. Site-directed mutagenesis was used to generate a chimera between the murine H-2K^b and the human HLA-A2 [H-2K^b/HLA-A2(C')]. The structure of this chimera is similar to H-2K^b except for the region around the deep C pocket, where residues at positions 9, 97 and 99 were substituted with those bulkier residues from HLA-A2. Peptide binding between this chimera and H-2K^b-binding peptides [VSV (52–59), OVA (257–264), and MCMV pp89 (168–176)], revealed that the deep C pocket of H-2K^b was crucial for high-affinity binding. While a peptide, VSV (52–59), was found to bind with severalfold lower 'affinity' to H-2K^b/HLA-A2(C') than to the wild-type H-2K^b, a VSV analogue with the tyrosine in position 5 (Tyr5) substituted with an alanine was found to bind with a similar 'affinity' to both MHC class I molecules. Computer-aided modelling of the H-2K^b/HLA-A2(C') complex indicates that the VSV (52–59) peptide probably binds to the chimeric MHC molecule with the peptide side chain of anchor residue Tyr5 pointing away from the groove. These results confirm a role of the individual pockets in determining peptide-binding affinity and specificity and suggest that this may be accomplished by changes in side-chain orientation.     

H-2, Ah, and aging: the immune response and the inducibility of P-450 mediated monooxygenase activities, xanthine oxidase, and lipid peroxidation in H-2 congenic mice on C57BL/10, C3H, and A strain backgrounds

The effects of beta-naphthoflavone (beta-NF, 80 mg/kg i.p. for 2 consecutive days) on P-450-dependent and -independent enzymes, lipid peroxidation and xanthine oxidase were investigated in 9 strains of young (3-month-old) male mice. Three H-2 congenic strains on each of three different genetic backgrounds were studied. The backgrounds were C57BL/10 (abbreviated as B10), C3H, and A strain mice. The reported longevities (weeks) as expressed in 10th decile of survivorship are significantly different among the H-2 congenic strains on each of these backgrounds: it ranges from 155 to 170 weeks in B10, from 138 to 150 in C3H and from 114 to 134 in A background mice. The inducibility of aryl hydrocarbon hydroxylase (AHH) with beta-NF was highest in B10, intermediate in C3H/He and non-inducible in other C3H mice and in all mice on the A strain background. Within the B10 background, inducibility of AHH varied widely among mice of different H-2 haplotypes: 549 +/- 34 (H-2k), 360 +/- 72 (H-2b) and 349 +/- 47 (H-2r) percent of the mean control values (n = 5; mean +/- S.D.), without change in activities of P-450-independent enzymes. In C3H mice the H-2k haplotype showed inducibility (213 +/- 34%), while other haplotypes, specifically H-2b and H-2j, did not. beta-NF increased the activities of xanthine oxidase in B10 and A background strains, without interbackground differences. Lipid peroxidation was significantly increased in A background strains and in an H-2 dependent manner. The relationship between Ah responsiveness and reported longevities of these nine strains is discussed.     

Complement C6 and C2 Biosynthesis in Syngeneic PVG/c− and PVG/c+ Rat Strains

A PVG rat strain with total deficiency of C6 and partial deficiency of C2 (PVG/c⁻), and a syngeneic control strain (PVG/c⁺), were used to study the production of extrahepatically synthesized complement. Livers of complement deficient rats were transplanted in sufficient rats (Tx−L). The C6 and C2 levels in Tx−L rats declined within 2 days to 25% and 30%, respectively, and remained stable for more than 6 weeks. To investigate the contribution of C6 synthesis by the liver, C6 sufficient livers were grafted in deficient rats (Tx+l). After an initial increase, with maximum C6 levels of 119% at 10 days following transplantation, the C6 levels decreased gradually and C6 was no longer detectable 28 days after transplantation. This decline in C6 levels was dependent on antibody production against C6. No significant change in the C3, C4, factor H and factor B levels was observed. Expression of C6 mRNA in the grafted PVG/c⁺ sufficient liver was comparable to the expression of C6 mRNA in control PVG/c⁺ livers while C6 mRNA expression in the transplanted PVG/c⁻ liver and the control PVG/c⁻ liver was lower. In conclusion, it was demonstrated in vivo that not only C6 but also C2 is synthesized extrahepatically in PVG/c rats.     

Maturation of the filaria Litomosoides sigmodontis in BALB/c mice; comparative susceptibility of nine other inbred strains.

When inoculated subcutaneously, the infective larvae of L. sigmodontis undergo complete development and produce a patent microfilaraemia in mice of the BALB background (BALB/c, BALB/K and BALB/B, with respectively the H-2d, H-2k et H-2b haplotypes). The most susceptible strain is BALB/c with all mice harbouring adult filariae and 47% of mice presenting with a patent microfilaraemia. Mice with the B10 background (B10, B10Br and B10D2, with respectively the H-2b, H-2k et H-2d haplotypes) are almost completely resistant to infection. Adult filariae were recovered from all mice of the CBA/Ca, CBA/HN, C3H/HeN, DBA/2N strains. However, the site and structural development of the parasite varied in each strain. Absence of microfilaraemia is associated with absent or abnormal spicules, reduced number of female filariae and small size of female filariae. These results show that the Major Histocompatibility Complex only modulates the developmental pattern of filariae within the limits imposed by background genes. Male CBA/HN and C3H/HeN were more susceptible to infection than female mice. Inverse phenomenon was observed with strains BALB/c; and, no host sex effect was seen in DBA/D2N.     

Expression of the H-2 Antigenic Complex on Murine Haematopoietic Stem Cells

We used hybridoma-derived monoclonal antibody to H-2K^k antigens and xenoantibodies to β₂-microglobulin (β₂) to study the expression of the H-2 antigenic molecular complex on murine hematopoietic stem cells and the effect of long-term culture in vitro on the expression of these antigens. Monoclonal anti-H-2K^k antibody produced potent complement-dependent inhibition of pluripotent (CFU-S), myeloid (CFU-C), and erythroid (CFU-E) stem cells from the bone marrow of C3H and AKR (H-2^k) mice and was without effect on stem cells from Balb/C (H-2^d) mice. Anti-β₂m xenoantibodies inhibited stem cells from all three strains. Stem cells could not be 'rescued' from the inhibitory effects of the antibodies by the addition of thymocytes to marrow cells after antibody treatment. Both the anti-H-2K^k monoclonal antibody and the anti-β₂m xenoantibodies produced potent inhibition of AKR (H-2^k) CFU-C that had been maintained in culture for up to 6 weeks. These results indicate that murine CFU-S, CFU-C, and CFU-E express H-2 antigens and that the expression of these antigens by CFU-C is not altered during long-term culture.     

Clonal dissemination of a toxin-A-negative/toxin-B-positive Clostridium difficile strain from patients with antibiotic-associated diarrhea in Poland

Objective To determine the incidence of toxin-A-negative/toxin-B-positive Clostridium difficile strains and their genetic relatedness in the feces of patients suffering from antibiotic-associated diarrhea (AAD) in Polish hospitals.
Methods C. difficile strains were cultured from patients' stool samples. The present study characterises these strains with respect to their cytopathogenicity on McCoy cells and the absence of toxin A despite a functional toxin B as determined with commercial test kits (Culturette Brand Toxin CD-TCD toxin A test and C. difficile Tox A/B test). In addition, PCR using different primer pairs aiming at non-repeating or repeating regions of the toxin A and B genes were used to confirm the findings. All toxin A^–B⁺ strains were genetically characterised by random amplification of polymorphic DNA (RAPD) analysis, PCR ribotyping and, in part, pulsed-field gel electrophoresis (PFGE) of DNA macrorestriction fragments.
Results We here present the presence of 17 toxin A^–B⁺ strains among 159 C. difficile strains (11%) isolated from fecal samples from 413 patients with antibiotic-associated diarrhea. All 17 strains possessed the toxin B gene, demonstrated a cytopathogenic effect on the McCoy cells, and were positive in the Tox A/B test. Molecular typing of these 17 C. difficile strains revealed that 7 of 17 (41%) toxin A^–/B⁺ C. difficile strains could not be discriminated. It appeared that these strains had a genotype that could not be distinguished from that of a Japanese control strain.
Conclusion Our observations imply that a particular genotype of toxin A^–B⁺ C. difficile has spread extensively, not only in Poland but possibly even worldwide.     

A CONTRIBUTION TO THE HEREDITY OF THE P.T.C. TASTE CHARACTER BASED ON A STUDY OF 845 SIB-PAIRS

1. 128 sibships comprising 489 sibs and 845 sib-pairs belonging to the Rárhi Bráhmin community of West Bengal have been studied for p.t.c . taste thresholds by the serial dilution method with a final sorting test.
2. Expectations on the basis of (A) the hypothesis of recessive inheritance of the 'non-taster' phenotype and (B) the hypothesis of chance combination of pairs without any influence of heredity have been compared with the observed data of sib-pairs.
3. Neither of the two hypotheses shows a satisfactory agreement (by the x² test) with the entire mass of observed data. The hypothesis (A), however, appears to be a much closer approach (x²= 17·5 and 20·55, 2 d.f.) to the facts than the hypothesis (B) which yields much higher x² values (x²= 87·11 and 86·93, 2 d.f.).
4. The extreme 'tasters' and 'non-tasters' when separated from the intermediate phenotypes show a very good agreement (x²= 4·340, 3 d.f.) with the hypothesis (A), but a wide divergence (x²= 75·892, 3 d.f.) from the hypothesis (B).
5. The intermediate 'tasters' and 'non-tasters', however, indicate merely a slightly nearer approach (x²= 18·45, 3 d.f.) to hypothesis (B) than to hypothesis (A) (x²= 26·69, 3 d.f.)
The author records his thanks to Dr N. Datta-Majumder, the Director, Department of Anthropology for providing the facilities for the work and to Dr E. C. Biichi, the Superintending Anthropologist for useful discussions. Thanks are also due to Sm. Lalita Ghosh for her sincere assistance.     

Oligoclonality of TCRint Cells with a Low Diversity of TCR Complementarity-Determining Region 3 in Mice with Graft- Versus-Host Disease

Conventional T cells (i.e. TCR^high) are generated by the main stream of T-cell differentiation in the thymus. However, primordial T cells (i.e. TCR^int) are generated by extrathymic pathways and an alternative intrathymic pathway. Since TCR^int cells contain self-reactive clones, the diversity of the T-cell antigen receptor (TCR) complementarity-determining region (CDR) 3 was examined. The predominant Vβ8.2⁺ clones among TCR^int cells were selected for DNA sequencing. Thymectomized, irradiated mice subjected to bone-marrow transplantation (BMT) were used; graft-versus-host disease (GVHD), B6→(B6 × C3H/He) F ₁ and syngeneic BMT, B6→B6. In these combinations, only TCR^int cells were generated. Vβ8.2⁺ cells with a low diversity of CDR3 of V-gene expanded in GVHD mice. Vβ8.2⁺ cells of TCR^int and TCR^high cells in normal mice were polyclonal, showing that the former has a lower diversity of CDR3 than the latter. The clonality of activated TCR^high cells was examined, in which CD3^high cells (bm12 mice) were injected into 1 Gy-irradiated B6 nude mice. Some Vβ8.2⁺ clones among TCR^high cells were expanding but the diversity of CDR3 was greater than that of CD3^int cells, despite the fact that the recognition site of the H-2 difference was smaller. Taken together with invariant usage of Vα14, these results suggest that TCR^int cells have a low diversity of CDR3 of Vβ genes.     

Non-H-2-associated genetic regulation of cytotoxic responses to hapten-modified syngeneic cells Effect on the magnitude of secondary response and helper T cell generation after in vivo priming

The present study investigates the role of non-H-2 genes in controlling generation of the H-2-restricted, T cell-mediated cytotoxic response against trinitrophenyl (TNP)-modified syngeneic cells (TNP-self). Spleen cells from C3H/He (H-2^k) or B10.BR (H-2^k) normal mice or from mice primed to TNP in vivo by skin painting with trinitro-chlorobenzene were used (a) for in vitro sensitization to TNP-self and (b) as a source of radioresistant helper cells for augmenting the TNP-self cytotoxic T lymphocyte (CTL) response generated by normal syngeneic spleen cells. Although spleen cells from unprimed mice from these two strains exhibited a comparable CTL response in a primary culture, a strong difference was observed in a secondary CTL response after in vivo priming. CTL activities generated in the secondary culture were much stronger in C3H/He than in B10.BR strains. This difference in the magnitude of secondary CTL responses was paralleled by generation of strong and weak helper cell activity in C3H/He and B10.BR, respectively. No detectable difference was observed between the two H-2^k strains in the lysability of target cells and ability of stimulating cells to activate the primed unirradiated cells and radioresistant helper cells. This genetic difference detected in the H-2^k haplotype was also demonstrated in the H-2^b haplotype, by using C3H.SW and C57BL/10 mice which bear non-H-2 background genes corresponding to C3H/He and B10.BR mice, respectively. These results indicate the existence of a control mechanism influenced by non-H-2 genes, in addition to the established H-2-linked gene control.     

Polygenic influences on the length of oestrous cycles in inbred mice involve MHC alleles.

Genetic influences on female reproductive cycles were analysed in histocompatibility-congenic strains of mice. Oestrous cycles of young, virgin mice of inbred-congenic strains, hybrid crosses (F1), and parental-hybrid backcrosses (F2) were monitored for 3 months. Oestrous cycles were categorized by length (inter-oestrous interval): 4, 5, 6, or 7-14 days. Mice with the following H-2 haplotypes had a greater proportion of 5-day oestrous cycles: H-2b, H-2r, H-2h2, H-2h4, and H-2i5. In contrast, the H-2k and H-2d haplotypes had mostly 4-day oestrous cycles. Influences of H-2 haplotype were seen on two genetic backgrounds, C57BL/10Sn and C3H. Non-H-2 alleles were also implied by different patterns of cycles between strains with the same H-2b haplotype: C57BL/10Sn with predominantly 5-day cycles vs. C57BL/6J with a mix of 4- and 5-day cycles. The genetic basis for strain differences was investigation in F1 hybrids and their backcrosses. F1 hybrids of an H-2b (C57BL/10Sn; 5-day cycles) and an H-2k (B10.BR; 4-day cycles) strain had mostly 5-day cycles, indicating dominance of an H-2b allele(s). However, F1 hybrids from the reciprocal B6 x B10 cross (both H-2b) also display a preponderance of 5-day cycles, indicating dominance of a non-H-2 autosomal allele from the C57BL/10Sn strain. Among F2 mice, a '4-day' phenotype segregated with homozygosity for the k haplotype (P < 0.05, chi 2). These findings demonstrate the influence of genetic differences at the major histocompatibility complex on oestrous cycles.     

Genetic control of resistance to Mycoplasma pulmonis infection in mice.

The differences in susceptibility of various inbred strains of mice to a highly pathogenic strain of Mycoplasma pulmonis CT (T2) has been known for some time. We assessed the genetic control of resistance to T2 infection. Tracheolung lavage samples and lungs of mice were assessed for T2 organisms after intratracheal injection of T2. We found that H-2b (C57BL/6 (B6) and H-2k B10.BR mice were resistant, whereas H-2b A.By, H-2k C3H/Bi, H-2k C3H/HeJ (C3H), and H-2b BALB.B mice were susceptible. We also typed individual B6C3F2 mice for H-2 and for resistance to T2 and observed that resistance to T2 infections is controlled by a single dominant gene not linked to H-2. Histologic examination revealed severe lung lesions typical of M. pulmonis infections in susceptible C3H mice, in contrast to minimal lung lesions in resistant B6 mice. No significant titers of local or systemic antimycoplasma antibodies were detected in either resistant or susceptible mice at 5 days postinfection. Macrophages taken from uninfected B6 or C3H mice failed to inhibit growth of T2 in vitro. However, macrophages from B6 mice did inhibit growth of T2 much better than C3H macrophages when harvested on day 5 of infection. Thus, there is an association between activation of macrophage bactericidal function and genetic resistance to growth of T2 organisms.     

Alteration of the T cell self-specificity repertoire by treatment with anti-Ia antibody during embryonic life

The effect of anti-Ia antibody on the development of murine neonatal self-Ia-reactive T lymphocytes in the thymus was studied. A C57BL/6 (B6) mouse pregnant with (B6 X C3H/He)F1 (B6C3F1) embryos was injected with monoclonal anti-I-Ek (m alpha I-Ek) antibody every other day starting from the 12th day of gestation. The mixed leukocyte culture reaction (MLR) responses of thymocytes from m alpha I-Ek-treated neonatal mice were assayed against adult B6 (H-2b), C3H/H3 (H-2k) or BALB/c (H-2d) splenic stimulator cells. The syngeneic MLR response of m alpha I-Ek-treated B6C3F1 neonatal thymocytes against C3H stimulator cells was augmented compared to that of untreated neonatal thymocytes. Experiments utilizing recombinant inbred strains of mice as well as monoclonal anti-Ia antibody blocking experiments suggested that the antigen(s) responsible for this augmentation of syngeneic MLR resided in the I-Ek molecule. The MLR response against B6 or BALB/c stimulator cells was not influenced by m alpha I-Ek treatment. We speculate that m alpha I-Ek antibody blocked the expression of I-Ek molecules in B6C3F1 embryos and this resulted in the alteration of T cell self-specificity repertoire in the thymus. Our results support the concept that Ia molecules play important roles for the elimination of self-reactive T lymphocyte clones in the thymus.     

Role of the H-2s haplotype in survival of mice after infection with Trypanosoma cruzi.

In studies of the resistance of inbred mice to infection with Trypanosoma cruzi Peru, mouse strain B10.S was the only strain which survived the infection resulting from the inoculation of 10(3) trypomastigotes. This is the only inbred mouse strain studied to survive infection. To investigate the effect of the H-2 haplotype on survival, C57BL/10 congenic mouse strains bearing H-2S recombinant haplotypes and mouse strains A.SWSn/J and SJL/J were tested for their ability to overcome the T. cruzi infection. None of the recombinant strains tested, including B10.S(7R), B10.S(8R), B10.S(9R), and B10.HTT, survived the infection, indicating that at least two or more regions of the H-2 locus must be H-2S to ensure survival. Strains A.SWSn/J and SJL/J with the H-2S haplotype did not survive, indicating that the genetic background outside the H-2 complex also influences survival. The congenic F1 hybrid (C57BL/10 X B10.S) F1 exhibited intermediate survival levels when compared with the parental strains, indicating that H-2S survival is affected by gene dosage. The F1 hybrid strain [B10.S(7R) X B10.S(8R)]F1, which possesses the complete H-2S haplotype in the trans configuration, did not survive T. cruzi infection, suggesting that H-2S-mediated survival does not operate by trans complementation.     

Ir gene control of the murine secretory IgA response to cholera toxin

In these experiments we examined the genetic control of the secretory IgA (sIgA) response to cholera toxin (CT) after CT feeding. Inbred, congenic and intra-H-2I region recombinant mouse strains were immunized with intragastric application of 10 micrograms CT on days 0 and 14. Samples of intestinal secretions and plasma were collected 1 week after the second dose and antibodies to CT measured in them by antigen- and isotype-specific enzyme-linked immunosorbent assay. In three different sets of H-2-congenic strains the intestinal IgA anti-CT response clearly depended on the H-2 haplotype rather than on background or IgH genes. H-2b (B10, A.BY/SnJ, C3H.SW) and H-2q (B10.T(6R), DBA/1J) strains were high responders, H-2k (B10.BR, C3H/He), H-2s (A.SW/SnJ) and H-2d (B10.D2) strains were low responders. Within the H-2 complex the intestinal IgA anti-CT response was mapped to the I-A subregion with the use of congenic intra-H-2I region recombinant strains: B10.A(3R) and B10.A(5R) were high responders and B10.A(4R), B10.MBR and B10.GD were low responders. Plasma IgG anti-CT after CT feeding paralleled the sIgA results. Surprisingly, the sIgA and plasma IgG anti-CT responses in individual mice of the various strains tested showed a highly significant positive correlation. We conclude that both the sIgA response and plasma IgG anti-CT response after CT feeding is controlled by the I-A subregion of H-2.     

Genetic Control of the Murine Cell-Mediated Immune Response In Vivo

Various inbred and congenic strains of mice were immunized with the linear terpolymer L-glutamic acid⁶⁰-L-alanine³⁰-L-tyrosine¹⁰ (GAT). Using a radioisotopic footpad assay to measure cell-mediated immunity in vivo, mice with H-2^a, H-2^b, H-2^d, and H-2^k histocompatibility alleles showed a positive reaction, whereas mice with H-2^P and H-2^S alleles failed to respond. The ability of 'responder'. lymphocytes to show an immune response resides in the thymus-derived (T) lymphocyte population. Unfractionated spleen cells from H-2^q nonresponder mice, on transfer, showed no reactivity, whereas T-cell-enriched preparations were active.