Immunity to leprosy. II. Genetic control of murine T cell proliferative responses to Mycobacterium leprae

T cell proliferative responses to Mycobacterium leprae were measured after immunization of mice at the base of the tail with antigen and challenging lymphocytes from draining lymph nodes in culture with M. leprae. This T cell response to M. leprae has been compared in 18 inbred strains of mice. C57BL/10J mice were identified as low responder mice. The congenic strains B10.M and B10.Q were found to be high responders, whereas B10.BR and B10.P were low responders. F1 (B10.M X C57BL/10J) and F1 (B10.Q X C57BL/10J) hybrid mice were found to be low responders, similar to the C57BL/10J parent, indicating that the low responsive trait is dominant. Whereas B10.BR mice were shown to be low responders to M. leprae, B10.AKM and B10.A(2R) were clearly high responders, indicating that the H-2D region influences the magnitude of the T cell proliferative response. Gene complementation within the H-2 region was evident. Genes outside the H-2 region were also shown to influence the response to M. leprae. C3H/HeN were shown to be high responder mice, whereas other H-2k strains, BALB.K, CBA/N, and B10.BR, were low responders. Gene loci that influence the T cell proliferation assay have been discussed and were compared to known background genes which may be important for the growth of intracellular parasites. Because mycobacteria are intracellular parasites for antigen-presenting cells, genes that affect bacterial growth in these cells will also influence subsequent immune responses of the host.     

A new lymphocyte alloantigen (Ly-10) controlled by a gene linked to the Lyt-1 locus

Spleen cells from a (BALB/c x C57BL/6)F1 mouse immunized with CBA/J spleen cells were fused with the myeloma cell line NS-1. One of the six established hybrid cell lines continuously secreted antibody that recognized a new antigenic specificity, tentatively called "Ly-10.1". This newly found antigen is expressed on thymocytes, on splenic T and B cells, on bone-marrow cells, and on the cells derived from brain, kidney and liver. It is also expressed on a continuous cell line, 416B, with stem-cell characteristics. The unique tissue distribution and, furthermore, a distinct strain distribution pattern distinguishes Ly-10.1 from any known murine lymphocyte alloantigen. On the basis of reactivity with cells of the C57BL/6-Lyt-1a congenic strain, one gene governing Ly-10 expression is assigned to the Lyt-1 region of chromosome 19.     

Genetic differences in BCG-induced resistance to Schistosoma mansoni are not controlled by genes within the major histocompatibility complex of the mouse.

Induction of nonspecific resistance to Schistosoma mansoni infection after the i.v. injection of viable BCG was investigated in outbred mice and a panel of inbred and H-2 congenic strains. Significant protection was induced in CF1, A/J, C57BL/6, C57BL/10, DBA/2, C57BR, and SJL mice. BALB/c mice were not protected whereas CBA and C3H mice expressed intermediate degrees of protection. Expression of the protective phenomenon is not controlled by genes within the MHC as shown by the marked differences in response between BALB/c and DBA/2 (H-2d) as well as between C57BR and C3H (H-2k) mice. H-2 congenic strains with C57BL/10 background (B10.A and B10.D2) were high responders. BALB.B10 mice carrying the high responder (B10) MHC on the nonresponder (BALB/c) background were not protected. The degree of splenic hypertrophy did not correlate with the expression of nonspecific resistance. These results demonstrate that, in addition to controlling specific immune responses, genetic differences influence the nonspecific protective phenomena related to BCG administration as well.     

An X-encoded alloantigenicity between BALB/c and C57BL/6 strains of mice

To detect minor barriers to histocompatibility that might be encoded on the X chromosome in mice, we grafted reciprocal sets of (C57BL/6xBALB/c)F1, (C57BL/6xDBA/2)F1, and (BALB/cxDBA/2)F1 mice with tail skin from the respective paternal inbred strain. Our histogenic analysis suggests that, compared with the C57BL/6 mouse strain, the BALB/c strain generates X-linked antigen loss. In contrast, we detected no X-linked histogenic differences between strains C57BL/6 and DBA/2, or DBA/2 and BALB/c. To localize this X-linked barrier to histocompatibility, we produced a panel of 25 [(BALB/cxC57BL/6)F1xC57BL/6]N2 males that were grafted with C57BL/6 skin to determine which carried the BALB/c-derived component(s) necessary for graft rejection. DNA marker analysis showed one region of overlapping BALB/c-derived X-chromosomal segments among the graft rejecters, suggesting that this antigen-loss haplotype ( H-hix(c), for histoincompatibility on the X chromosome, c haplotype) may be restricted within the DXMit55 to the Xq telomere interval (which excludes only the centromeric tip of the X). Further backcrossing of H-hix(c) to C57BL/6 resulted in fewer rejecter mice than expected by the N4 generation, suggesting that a second, unlinked locus is also involved in this X-linked alloantigenicity. The vigorous rejection of male (C57BL/6xBALB)F1 and female (B6.C- H2(d)xC57BL/6)F1 skin by (BALB/cxC57BL/6)F1 males, as well as the assessment of markers on Chromosome 17 among N2 and N4 graft-recipient males, suggests that this second locus is H2, and that H-hix(b)-encoded alloantigens require both H2(b) and H2(d)-encoded presentation molecules for efficient graft rejection.     

A new cross-reactive idiotype-defined family in the phthalate humoral immune response of mice. I. Linkage of VH-Xmp to IgCH allotype locus and mapping with respect to other known VH genes

A cross-reactive idiotype family was previously identified from a very large library of phthalate-specific hybridoma clones. The prototype of this idiotype family is the hybridoma, 2E9, secreting an IgM antibody with phthalate specificity. A portion of both primary and secondary anti-phthalate antibodies elicited in all BALB/c mice tested expresses the 2E9 cross-reactive idiotype. This idiotype has now been found in the anti-phthalate antibodies of several other inbred strains of mice (A/HeHa, DBA/2, and C3Hf/HeHa) tested but not in C57BL/6 mice. Anti-phthalate antibodies elicited from congenic mice BC.8, which express the same IgCH allotype as BALB/c mice but possess C57BL/6 genetic background, contain the 2E9 cross-reactive idiotype, whereas this idiotype is not expressed on the anti-phthalate antibodies derived from another congenic mouse CB.20, which expresses a C57BL/6 IgCH allotype and a genetic background of the BALB/c strain. These results indicate that the gene controlling the 2E9 idiotype is closely linked to the IgCH allotype locus. The 2E9 cross-reactive idiotype was also found in all of the F1 mice (BALB/c X C57BL/6) tested, and the level of expression of this idiotype in the F1 mice was quantitatively equivalent to the allotype/idiotype homozygous mice. The expression of the 2E9 idiotype in the phthalate repertoire has been followed in 12 different wild mouse populations. As expected, the 2E9 idiotype was observed in a large proportion of the wild mouse strains. Surprisingly, several examples of nonconcordance in the expression of idiotype and allotype were observed in these mice. One likely explanation for the linkage breakdown is a crossing over of the heavy chain constant and variable region gene complexes. In the SM/J inbred strain of mice, where such a crossover has occurred, nonconcordance between allotype and 2E9 idiotype expression was demonstrated. By using the recombinant inbred BXD strains of mice, the VH gene encoding the 2E9 idiotype has been mapped with respect to other known VH gene families. Relative to other VH genes the VH-Xmp is situated very close to the IgCH gene region.     

Genetic control of immune responses to the 18-kDa protein of Mycobacterium leprae. Different TH1 subsets may be involved in proliferative and delayed-type hypersensitivity responses.

In vitro and in vivo responses to the 18-kDa protein of Mycobacterium leprae have been analysed in different strains of mice. Lymphocytes from BALB/cJ (H-2d), BALB.B (H-2b), B10.BR (H-2k), and B10.M (H-2f) mice primed with 18-kDa protein yielded high T cell proliferative responses, while those from C57BL/10J (H-2b) mice yielded lower responses. Both H-2 and non-H-2 genes contributed to the magnitude of responsiveness. F1 mice from high and low responder strains showed high responsiveness to the 18-kDa protein. Supernatants from lymph node cell cultures prepared from 18-kDa protein-immunised BALB/cJ, B10.BR, and C57BL/10J mice contained IL-2 but no IL-4, indicating that activated T cells from both high and low responder mice were of a TH1 phenotype. Cell cultures from low responder C57BL/10J mice produced less IL-2 than those from high responders. The low responsiveness to the 18-kDa protein in proliferative assays might be due to a low frequency of antigen-specific T cells in the C57BL/10J mouse strain. BALB/cJ, C57BL/10J, and F1 (BALB/cJ x B10.BR) mouse strains were tested for in vivo DTH reactions to the 18-kDa protein. All strains, including C57BL/10J, were high DTH responders. Although DTH effector cells and 18-kDa protein-specific proliferative T cells belong to the TH1 subset, our data comparing high and low responder status indicate that distinct TH1 subpopulations are stimulated in response to the 18-kDa protein of M. leprae.     

Hybrid resistance to BALB/c plasmacytomas. I. Resistance to MPC-11 controlled by a locus not linked to H-2.

Genetic control of hybrid resistance to the BALB/c plasmacytoma MPC-11 was investigated. The results indicate that a single dominant autosomal gene or gene complex, which segregates independently of H-2 and the coat color c and b-loci, controls resistance to this tumor. This gene has the same strain distribution pattern in the CXB Bailey recombinant inbred strains as three unlinked genes, H-2, Ly-4, and Ea-4. It is possible, therefore, that it could be linked to either of the latter two loci. Strains that carry a positive allele for resistance are C57BL/10 and all of its congenic resistant partners tested, C57BL/6, C57L, C57BL/Ks, AKR, and DBA/1. BALB/c and its congenic resistant partners are presumed to carry a negative allele of the gene for resistance to MPC-11. Strains such as SJL, DBA/2, and A and its congenic resistant partners, which form susceptible hybrids with BALB/c, could carry either the negative allele of the gene for resistance, like BALB/c, or could carry both a positive allele of the gene and some other gene conferring susceptibility on the hybrids. Heterozygosity within the H-2 complex increases resistance only in the presence of this non-H-2 linked gene for resistance, and the effect maps to the left of the H-2D region.     

Genetic Determination of the Developmental Program for Mouse Liver β-GALACTOSIDASE: Involvement of Sites Proximate to and Distant from the Structural Gene

The identification and mode of action of genetic loci that program gene expression during development are important for understanding differentiation in higher organisms. Previous work from this laboratory has identified two patterns for the postnatal development of liver beta-galactosidase among inbred mouse strains: type I, where activity levels remain constant after about 30 days of age, is found in strains DBA/2J, CBA/J, and BALB/cJ, among others; type II, where activity levels increase between 25 and 50 days of age to reach a new adult level, is found in strain C57BL/6J and related strains. It has been shown that the type I vs. type II developmental difference between strains C57BL/6J and DBA/2J is due to variation at a locus, Bgl-t, that maps with the beta-galactosidase complex, [Bgl], on chromosome 9. In the present study, we have confirmed the existence of Bgl-t as a temporal locus within [Bgl] by analysis of both a congenic strain carrying the beta-galactosidase complex of strain CBA/J in the C57BL/6J genetic background and a cross of strains CBA/J and C57BL/6J. The existence of additional temporal loci for beta-galactosidase that segregate independently of the structural gene and participate in determination of the type I vs. type II difference was revealed by analysis of: (1) a congenic strain containing the beta-galactosidase complex of strain BALB/cJ in the C57BL/10Sn background; (2) recombinant inbred lines derived from progenitor strains C57BL/6ByJ and BALB/cByJ; and (3) a genetic cross between strains C57BL/6ByJ and BALB/cByJ. Thus, for these pairs of strains, the type I vs. type II developmental difference is due to variation at a temporal locus (or loci) unlinked to the enzyme structural gene, and not at Bgl-t. These facts, together with information gathered from an examination of the distribution of beta-galactosidase phenotypes among over 100 inbred strains (Breen, Lusis and Paigen 1977), have led us to conclude that the postnatal developmental pattern for liver beta-galactosidase is determined by a set of interacting temporal genes. One of these, Bgl-t, is located within [Bgl], and one or more are separable from [Bgl] by recombination. A possible mode of interaction among the temporal and instructural loci is suggested.     

Genetic regulation of early survival and cyst number after peroral Toxoplasma gondii infection of A x B/B x A recombinant inbred and B10 congenic mice

Genetics of two traits, survival and brain cyst number after peroral Toxoplasma gondii infection, were studied by using recombinant inbred strains of mice derived from resistant A/J (A) and susceptible C57BL/6J (B) progenitors, F1 progeny of crosses between A/J and C57BL/6J mice, and congenic mice (B10 background). Analysis of strain distribution pattern of survival of A x B/B x A recombinant mice indicated that survival is regulated by a minimum of five genes. One of these genes appears to be linked to the H-2 complex and another is related to an as yet unmapped gene controlling resistance to Ectromelia virus. Associations of defined traits with resistance or susceptibility to Toxoplasma cyst formation were also analyzed. Cyst number is regulated by a locus on chromosome 17 within 0 to 4 centimorgans of the H-2 complex (p = 0.001). Mice with the H-2a haplotype are resistant and those with the H-2b haplotype are susceptible. This analysis also indicated that the Bcg locus on chromosome 1 may effect cyst number (map distance = 12 centimorgans, p = 0.05). Resistance to cyst formation is a dominant trait. To analyze relative roles of H-2 and Bcg loci on cyst numbers, C57BL10 (B10)-derived congenic strains of mice with known H-2 and Bcg type were studied. These studies indicated that the H-2 complex locus has the primary effect on cyst number.     

Dimethylnitrosamine metabolism: II. In vitro activation of dimethylnitrosamine by hepatic and renal tissues from crosses among BALB/c, DBA and C57BL mice

Crosses among BALB/c, C57BL and DBA mice were performed to investigate the genetic mechanisms involved in metabolism of DMN by renal and hepatic tissues. Liver S-9 fractions from parental strain DBA had the greatest potential to activate DMN and liver fractions from parental strain BALB/c had the lowest. No age or sex-related differences were observed within strain. Crossing of either C57BL or DBA to BALB/c mice resulted in F1 hybrids with liver microsomal enzymes that gave results similar to the BALB/c parental strain. There were no sex or age differences within crossbred strains in the potential of liver to activate DMN. In contrast male DBA and C57BL parental mice renal S-9 fractions did not differ significantly from each other but did differ significantly from male BALB/c renal fractions and from female and immature animals of all strains. Crossing of either DBA or C57BL mice with BALB/c mice resulted in male F1 hybrids whose renal S-9 fractions did not differ significantly from males of the parental BALB/c strain. In all instances, male renal S-9 fractions had a significantly greater potential to activate DMN than female or immature animals. F1 DBA X C57BL hybrids had renal S-9 fractions that did not differ significantly from the parental strains. These data suggest that the gene(s) for low DMN metabolism of BALB/c mice are apparently dominant over the genes from both DBA and C57BL. The exact genetic or physiological mechanism needs further elucidation.     

Sex and strain differences of mouse variant salivary proteins

Proteins of the mouse saliva are resolved into about 20 discrete bands by polyacrylamide gel electrophoresis. Sexual dimorphism and monomorphism were found in a subset (Msp-1) of these salivary proteins from different inbred strains. This sexual dimorphism involves a fast moving band (F-type) and a slow moving one (S-type). Mature males of seven strains (A/J, AKR, CBA/J, C3H/HeN, A/Sn, B10.A, and B10.BR) exhibit the S phenotype while mature females of these strains were typed as F. Sexually immature males and females of these strains were uniformly typed as F, but at puberty (5-6 weeks of age) the phenotype of the males switched to type S, while the phenotype of the females remained the same. This switch to type S at puberty did not take place in males of four strains (BALB/cAnn, B10.D2, C57BL/6, and C57BL/10); therefore, we conclude that these strains were sexually monomorphic with regard to Msp-1. The phenotype of mature males of C3H/HeN reverted to type F following castration, whereas castrated males and mature females switched to type S in response to testosterone administration. The testosterone treatment had no effect on the type S phenotype of males and females of the sexually monomorphic BALB/cAnn strain. The male-specific type S phenotype of Msp-1 was seen only in mice with H-2 haplotype a or k; thus an association with H-2 haplotype was suggested. All F1 males of reciprocal crosses involving the sexually dimorphic and monomorphic strains (e.g., C3H/HeN X BALB/cAnn) demonstrated the type S phenotype at puberty.     

The<Emphasis Type="Italic"> Sr1</Emphasis> gene that controls diversity of the anti-inulin antibody response maps to mouse chromosome 14

Previous studies demonstrated that the diversity of the antibody response of mice to the inulin (In) determinant of bacterial levan is regulated by the gene Spectrotype Regulation 1 ( Sr1). BALB/c mice produce a monoclonal anti-In response as shown by isoelectric focusing analysis. In contrast, the anti-In antibody response of (BALB/cxC57BL/6)F1 mice is significantly more heterogeneous. We performed a backcross and a genome-wide scan with microsatellite markers and found that Sr1 is tightly linked to D14Mit121 on chromosome (Chr) 14. This location for Sr1 was supported by analysis of CXB Recombinant Inbred strains. We further confirmed this by finding that the Chr 14 congenic mouse strain B6.C-H8 lacks the C57BL/6 allele of the Sr1 gene, indicating that Sr1 is located in the segment of Chr 14 replaced with BALB/c donor DNA. These data place Sr1 near to or coincident with the Tcra/Tcrd T-cell receptor gene complex and suggest a role for T cells in diversifying the anti-In response.     

Comparison of patterns of hybrid resistance to the BALB/c plasmacytomas LPC-1 and MPC-11

Summary Patterns of genetic control of hybrid resistance to the BALB/c plasmacytoma LPC-1 were studied for comparison with those to MPC-11, a plasmacytoma investigated previously. The overall patterns of hybrid resistance to the two tumors were similar, i.e., hybrids between BALB/c and BALB congenic resistant (CR) strains, A and A CR strains, SJL and DBA/2 were as susceptible to LPC-1 as BALB/c mice themselves, whereas hybrids between BALB/c and AKR, C57BL/Ks, DBA/1, C57BL/6 (B6), C57BL/10 (B10) and B10 CR strains were resistant to LPC-1 as previously shown with MPC-11. Heterozygosity within the H-2 complex alone was insufficient for resistance to either tumor. Among hybrids between BALB/c and the B10 CR strains, however, the presence of certain H-2 haplotypes influenced the degree of resistance seen and this H-2 effect was different for the two tumors. A sex effect on resistance to LPC-1, but not to MPC-11, was seen among F₁ hybrids between BALB/c and DBA/1 although not in any other F₁ hybrids. Among ((B10×BALB/c)F₁×BALB/c) and (BALB/c×(B10×BALB/c)F₁) and ((BALB/c×B10)F₁×BALB/c) and ((BALB/c×B10)F₁×BALB/c) backcross mice, however, significantly more males than females were resistant to LPC-1 and the results of this study are compatible with the idea that in F₁ hybrids between BALB/c and B10, resistance to LPC-1 is controlled by two dominant autosomal genes, one of which is sex-limited and neither of which is linked to H-2. In contrast, hybrid resistance to MPC-11 in this cross is controlled by a single gene. Cross-protection experiments indicated that the two tumors share at least one tumor-associated transplantation antigen.     

Streptobacillus moniliformis epizootic in barrier-maintained C57BL/6J mice and susceptibility to infection of different strains of mice

We report a Streptobacillus moniliformis epizootic in barrier-maintained SPF mice. Although various inbred and F1 hybrid strains of mice have been kept in this animal facility, only C57BL/6J Han [corrected] mice showed clinical signs of disease. During the course of the epizootic, 825 breeding animals (approximately 36% of the breeders) died or had to be killed because of severe clinical signs. Although sequential treatment with ampicillin and chlortetracycline gave good therapeutic results, the animal facility was vacated in order to exclude any risk of cross-contamination of the other rodent colonies in our institute. The source and route of transmission of S. moniliformis could not be elucidated. To investigate strain dependent differences experimental infection of different strains of mice with our S. moniliformis isolate was performed. After oral infection only C57BL/6J showed the typical signs of a cervical lymphadenitis and gave an immunological response. BALB/cJ, C3H/He, DBA/2J, CB6F1 and B6D2F1 mice were not affected except in two cases of DBA/2J and B6D2F1 mice where seroconversion was observed. After intravenous infection of C57BL/6J, DBA/2J [corrected] and BALB/cJ all animals showed positive titers in the indirect immunofluorescence test (IIF). One hundred percent of the C57BL/6J, forty percent of the DBA/2J, and none of the BALB/cJ mice developed severe symptoms. The results demonstrate that the susceptibility to streptobacillosis is predominantly influenced by genetic factors.     

Immune response to the H-X antigen on P815-X2

In a preceding report, the detection of an H-2-linked immune response to the H-X ^d antigen on the P815-X2 mastocytoma was demonstrated by the significantly increased survival of (C57BL/6 × DBA/2)F₁ (B6D2F1) male hybrids (H-X ^b ) compared with female siblings (H-X ^{b/H-X d} ) after injection with the histocompatible tumor (H-X ^d ). This interpretation was supported by the absence of this sex effect in reciprocal D2B6F1 hybrids (H-X ^d and H-X ^{d/H-X b} ). Additional findings presented in this paper support the conclusion that this sex effect is due to a true immunological response to H-X ^d : (a) Reciprocal (DBA/2 × C57BL/6 H-2 mutant)F₁ hybrids, as well as D2B6F1, failed to exhibit the sex effect: (b) the demonstration of the sex effect in (BALB/c × DBA/2)F₁ and (BALB/c-H-2 ^dm2 × DBA/2)F₁ hybrids and in (C57BL/10 × DBA/2)F₁ hybrids was consistent with the known H-X incompatibilities between the strains BALB/c and DBA/2 and C57BL/10 and DBA/2, respectively, previously demonstrated by skin grafting; and (c) the sex effect was not abrogated by castration of male B6D2F1 hybrids. Variability in the presence or absence of the sex effect was observed in various [recombinant inbred (RI) × DBA/2]F₁ hybrids and may be attributed to the influence of a regulatory non-H-2 gene which is closely linked to the gene coding for mouse kidney-androgen-regulated protein (KAP) but androgen-independent, or to variability in inheritance of the H-X ^b allele among the RI lines. It is proposed that the P815-X2 model may be utilized to type RI lines derived from a cross between C57BL/6 and DBA/2 for their H-X genotypes.Abbreviations B C57BL/6 origin allele - B6 C57BL/6 - B10 C57BL/10 - B6D2F1 (C57BL/6 × DBA/2)F₁ - B6 ^m D2F1 (C57BL/6 H-2 mutant × DBA/2)F₁ - bm10 B6.C-H-2 ^bm10 - C BALB/c - D DBA/2 origin allele - D2 DBA/2 - dm2 BALB/c-H-2 ^dm2 - H-X X chromosome-determined histocompatibility antigen of the mouse - Ir gene, immune response gene - KAP kidney androgenregulated protein - MST median survival time - RI recombinant inbred - SDP strain distribution pattern     

Genetic analysis of strains C57BL/6J and BALB/cJ for Ath-1, a gene determining atherosclerosis susceptibility in mice

We previously reported that mice have at least one major gene determining atherosclerosis susceptibility, Ath-1. Susceptible alleles of Ath-1 are found in strain C57BL/6J and are associated with relatively low levels of high-density lipoprotein cholesterol (HDL-C) when these mice are fed an atherogenic diet. Resistant alleles of Ath-1 are found in strains C3H/HeJ and BALB/cJ and are associated with relatively high levels of HDL-C. Data reported earlier from the set of seven recombinant inbred (RI) strains, derived from C57BL/6By and BALB/cBy, showed that these parental strains differed at Ath-1. However, due to the limited number of RI strains, it was not possible to determine with certainty whether Ath-1 was the only major gene determining atherosclerosis susceptibility in these two strains or to determine its map position accurately. In this report, examination of F1, F2, and backcross progeny from a cross between C57BL/6J and BALB/cJ demonstrates that Ath-1 is the major gene determining atherosclerotic lesion formation and HDL-C levels in female mice. The data from male animals suggest that environmental factors or modifying genes also influence male HDL-C levels and thus partly obscure the Ath-1 phenotype. HDL-C levels in F1 progeny resemble the BALB/c parent. The data from the cross provide confirmatory evidence that Ath-1 is linked to Alp-2 on chromosome 1 with a map distance of 4.8 +/- 2.3 (SE). Combining these data with a previous cross between strain C57BL/6 and strain C3H/HeJ gives a map distance between Ath-1 and Alp-2 of 4.9 +/- 1.8 based on 7 crossovers found among 144 tested chromosomes.     

Susceptibility to immunosuppression by ultraviolet B radiation in the mouse

Irradiation with ultraviolet B (UVB; 290–320 nm) initiates systemic immunosuppression of contact hypersensitivity (CHS). UV dose-responses for suppression of CHS to trinitrochlorobenzene were established in 18 strains of inbred mice. Three phenotypes with significantly different susceptibilities to UV suppression were identified. The phenotypes were: high (HI) susceptibility, 50% suppression with 0.7–2.3 kJ/m² UV (C57BL/6, C57BL/10, and C57L and NZB females); low (LO) susceptibility, 50% suppression with 9.6–12.3 kJ/m² UV (BALB/c, AKR, SJL and NZW), and intermediate (INT) susceptibility, 50% suppression with 4.7–6.9 kJ/m² UV (DBA/2, C57BR, C3H/HeJ, C3H/HeN, CBA/N and A/J). UV suppression was not correlated with skin pigmentation or with the magnitude of the CHS response in non-irradiated animals. Major histocompatibility complex (MHC) haplotype was not correlated with UV suppression in MHC congenic strains B10.D2/oSnJ, B10.D2/nSnJ, B10.BR/SgSnJ, and A.BY/SnJ. There were no sex differences in UV suppression in BALB/c, C57BL/6, or NZW animals. In the autoimmune NZB strain, however, male mice (LO) were seven times less sensitive to UV suppression than NZB female mice (HI). Both sexes of (NZB × NZW)F₁ and (NZW × NZB)F₁ mice were HI, supporting dominance of HI over LO. Thus there are genetic factors and interacting sex-limited factors determining susceptibility to UV suppression. These findings may be of relevance to UV-related diseases such as photosensitive lupus and skin cancer. Correspondence to: F. P. Noonan.     

H-41, a new minor histocompatibility locus. I. Histogenetic analysis

The B10.STA12 mouse congenic line inherited from the wild mouse parent not only the H-2w13 haplotype but also an allele at a minor H locus, which we designate H-41. This allele (H-41a) differentiates the B10.STA12 line from B10.STA10 and B10.LIB55, which carry identical H-2w13 haplotypes but a different H-41 allele (the H-41b, also present in the background strain C57BL/10Sn). The B10.STA12 and B10.STA10 lines reject each other's skin grafts and generate cytolytic T lymphocytes (CTL) after in vivo immunization and in vitro restimulation with cells of the partner strain. The B10.STA12 anti-B10.STA10 CTL react with B10.STA10, B10.LIB55, and B10.STA39 target cells and with cells of F1 hybrids between the responder strain B10.STA12 and strains C57BL/6, C57BL/10, C57L, BALB/c, A, AKR, WB, DBA/1, and DBA/2 but fail to react with (C3H x B10.STA12) F1 and (CBA x B10.STA12) F1 cells. The B10.STA10 anti-B10.STA12 CTL react with B10.STA12, B10.P, and C3H.NB cells but fail to react to (B6 x B10.STA10) F1 target cells. The CTL reactivity in both combinations is Dp restricted. The B10.STA10 anti-B10.STA12 CTL exhibit, in addition, a cross-reactivity with B10.SAA48 cells that may be directed at one of the alloantigens controlled by the H-2 haplotype of this strain.     

A murine locus on chromosome 18 controls NKT cell homeostasis and Th cell differentiation

Th cell differentiation is a critical event in the adaptive immune response. C57BL strains develop predominant Th1 responses while BALB/c develops a predominant Th2 response. To identify quantitative trait loci controlling this variation, we performed Th1/Th2 differentiation assays of F(1) x BALB/c progeny. A single strong quantitative trait locus was identified on chromosome 18, with weaker effects detectable on chromosomes 5, 12, and 14. By preparing a congenic BALB.B10.D2c18 strain, we were able to demonstrate that this single locus was sufficient to "repolarize" spleen cell cultures. This difference was not due to intrinsic differences in CD4(+) T cells. Rather, introgression of the chromosome 18 locus into BALB/c disrupted Va14Ja18 NKT cell homeostasis resulting in the almost complete absence of this T cell subset. Taken together, these data indicate that genes within chromosome 18 control strain-dependent development of Va14Ja18 NKT cells.     

Murine Prkdc polymorphisms impact DNA-PKcs function

Polymorphic variants of DNA repair genes can increase the carcinogenic potential of exposure to ionizing radiation. Two single nucleotide polymorphisms (SNPs) in Prkdc, the gene encoding the DNA-dependent protein kinase catalytic subunit (DNA-PKcs), have been identified in BALB/c mice and linked to reduced DNA-PKcs activity and mammary cancer susceptibility. We examined three additional mouse strains to better define the roles of the BALB/c Prkdc SNPs (R2140C and M3844V). One is a congenic strain (C.B6) that has the C57BL/6 Prkdc allele on a BALB/c background, and the other is a congenic strain (B6.C) that has the BALB/c variant Prkdc allele on a C57BL/6 background. We also examined the LEWES mouse strain, which possesses only one of the BALB/c Prkdc SNPs (M3844V). Our results demonstrate that both Prkdc SNPs are responsible for deficient DNA-PKcs protein expression, DNA repair and telomere function, while the LEWES SNP affects only DNA-PKcs expression and repair capacity. These studies provide insight into the separation of function between the two BALB/c SNPs as well as direct evidence that SNPs positioned within Prkdc can significantly influence DNA-PKcs function involving DNA repair capacity, telomere end-capping, and potentially cancer susceptibility.