Normal HBsAg presentation and T-cell defect in the immune response of nonresponders

Lymphocytes from nonresponders to HBsAg fail to proliferate in vitro in the presence of HBsAg-pulsed antigen presenting cells. We studied four pairs of major histocompatibility complex (MHC)-matched, mixed lymphocyte reaction-negative individuals discordant for HBsAg response. For each pair, responder lymphocytes proliferated in the presence of nonresponder antigen-pulsed antigen presenting cells. Respondera nd nonresponder antigen presenting cells were equally effective. There was no evidence for inhibition of responder T-cell proliferation by nonresponder lymphocytes or antigen presenting cells. The defect is thus in the helper T cells of nonresponders and not in the antigen processing or binding of processed peptides to MHC molecules on antigen presenting cells.     

Helper effects required during in vivo priming for a cytolytic response to the H-Y antigen in nonresponder mice

Induction of H-Y-specific cytotoxic T lymphocyte (CTL) responses in nonresponder female mice was attempted by i.v. injection of allogeneic male cells, followed by in vitro restimulation of recipient spleen cells with syngeneic male cells. Responses were obtained only in two strain combinations in which the recipients, although phenotypically nonresponders, carried responder alleles at class I major histocompatibility complex (MHC) loci, and the immunizing cells differed from the recipients at class II MHC loci. The two positive strain combinations were B10.A(2R) anti-B10.A(4R), and B10.GD anti-B10.D2(R101). In the first combination, both recipient and donor are nonresponders to H-Y, and the CTL are induced via a bystander effect of another CTL response to a previously undetected minor histocompatibility (H) antigen. This "carrier" antigen can only induce CTL against H-Y and itself when the immunizing cells express class II MHC molecules. Furthermore, the presence of H-Y and the carrier antigen on the same cell is a prerequisite for the generation of H-Y-specific CTL. In the second combination, the recipient is a nonresponder, whereas the donor is a responder. The two strains differ at only E alpha and E beta class II MHC loci. For the induction of CTL, H-Y and the foreign E molecule must be expressed on the same cells. Thus, the B10.D2(R101) cells that express E molecules on their surface probably provide the E-nonexpressor B10.GD recipients with a stimulus for the generation of H-Y-specific T helper cells. The data are consistent with the notion that antigen-specific class II MHC-restricted T helper cells are involved in the initiation of CTL responses to minor H antigens.     

Specific binding of T lymphocytes to macrophages. V. The role of Ia antigens on Mphi in the binding.

The effect of anti-Ia alloantiserum on the capacity of selected peritoneal exudate lymphocytes (selected PEL) to bind to antigen-pulsed F1 (responder x nonresponder) macrophages was investigated. With the use of selected PEL for antigens under Ir gene control, it was shown that anti-Ia serum to the responder haplotype blocked adherence of selected PEL to antigen-pulsed macrophages whereas anti-Ia serum to the nonresponder haplotype did not. The target cell of the anti-Ia alloantiserum appeared to be the macrophage because anti-13 Ia in contrast to anti-2 Ia did not inhibit binding of F1 (2 x 13) DNP-GL selected PEL to DNP-GL pulsed strain-2 Mphi (responder strain). Taken together with previous experiments that indicate that an antibody to the native protein antigen employed is unable to block specific binding, the present results suggest that T cells may recognize fragments of exogenous antigen in association with Ia molecules.     

Genetic control of responses to bacterial lipopolysaccharides in mice. II. A gene that influences a membrane component involved in the activation of bone marrow-derived lymphocytes by lipipolysaccharides.

C3H/HeJ mice contain a defect in a single autosomal locus which is not linked to the H-2 histocompatibility or the heavy chain allotype loci that restrict immune, mitogenic, and polyclonal responses to bacterial lipopolysaccharides (LPS). Adult thymectomized C3H/HeJ mice that have been irradiated and reconstituted with C3HeB/FeJ bone marrow cells respond well to LPS. Cell-mixing experiments using C3H/HEJ-C3HeB/FeJ spleen cultures show that the failure of C3H/HeJ spleen cells to support responses to LPS is not due to nonspecific or LPS-induced suppressive events, or the lack of accessory cell types. C3H/HeJ and C3HeB/FeJ spleen cells bind LPS and respond to other B cell mitogens equally well. We suggest that the B lymphocytes of C3H/HeJ mice have a defect in a membrane component that is activated via interaction with LPS, and initiates the intracellular events that lead to cell proliferation.     

The functional helper T cell repertoire specific for L-glutamic acid60-L-alanine30-L-tyrosine10 (GAT)

Experiments have been carried out to examine the potential helper T cell repertoire specific for the random terpolymer GAT on responder, nonresponder, and (responder x nonresponder)F1 murine strains. The ability of GAT-MBSA immunized T cells to collaborate with DNP-specific primary and secondary B lymphocytes of each strain in response to the antigen DNP-GAT was tested with the splenic fragment culture system. The results of these experiments show that there are GAT-specific T lymphocytes in the responder, nonresponder, and F1 strains but that these 3 GAT-specific T cell populations differ in their collaborative potential. In sum, these findings present new evidence that the nonresponder status to the terpolymer GAT is due, in part, to a functional deletion of helper T cells capable of recognizing the antigen in the context of the nonresponder haplotype. Further, a new responsive phenotype is evidenced when F1 secondary B cells are stimulated in nonresponder GAT-MBSA-primed recipients. In this case, rather than the IgG1 responses observed in such strain combinations to other antigens such as DNP-Hy or DNP-Gl phi 9, only IgM responses were obtained. This new phenotype may be the result of GAT-specific suppression of isotype switching by B cells bearing the nonresponder cell surface alloantigens.     

Macrophage-lymphocyte clusters in the immune response to soluble protein antigen in vitro. VII. Genetically restricted and nonrestricted physical interactions.

We have assessed the genetic restrictions on physical interactions between macrophages and central lymphocytes and between central and peripheral lymphocytes in antigen-specific macrophage-lymphocyte clusters with respect to I-region differences of inbred strains 2 and 13 guinea pigs. When using lymphocytes from guinea pigs immunized with DNP-OVA or DNP-GL in CFA, the antigen-specific interaction between central lymphocyte and macrophage requires that both cells be derived from animals syngeneic at the I-region of the major histocompatibility complex. In studies using antigens, the responses to which is under the control of MHC-linked Ir genes, macrophages from the responder, but not from the nonresponder parental strain support cluster formation with responder x nonresponder F1(2 X 13) T cells. In contrast, the physical interactions between central and peripheral T lymphocytes are not restricted by the I-region of the MHC and the peripheral lymphocyte need not be from an animal immune to the antigen used to drive macrophage central lymphocyte interactions.     

Acquisition of an anti-idiotypic cytotoxic T lymphocyte repertoire in B cell-transferred or tetraparental bone marrow chimeric mice

In previous studies we showed that major histocompatibility complex-restricted cytotoxic T lymphocytes (CTL) specific for the cross-reactive idiotype (CRI) of MOPC-104E myeloma protein could only be induced in BALB/c or BAB-14 mice which have the ability to produce the CRI, but not in C.AL-20 or C.B-20 mice which have no ability to produce the CRI. The strong correlation between CRI-specific CTL responder strains and CRI producers supports the idea that the VH gene products are intrinsic primary antigenic stimuli for the generation of the anti-idiotypic CTL. To investigate the role of B lymphocytes in the selection of T lymphocyte repertoire, the purified B cells of CRI producer strains were repeatedly injected into anti-CRI CTL nonresponder neonatal mice. CRI-specific CTL activity was successfully induced in the CRI nonproducer mice only when they were exposed to CRI producer strain B lymphocytes from neonatal life. When the CTL nonresponder adult mice received CRI producer B lymphocytes, the nonresponder phenotype was not changed into the responder phenotype. Inducibility of CRI-specific CTL was also analyzed in tetraparental bone marrow chimeras. When CRI nonproducer bone marrow cells repopulated along with CRI producer bone marrow cells, the anti-CRI CTL of CRI nonproducer origin were generated. Adaptive differentiation of haplotype preference was also observed. When these observations are taken collectively, we see that the anti-idiotypic T lymphocyte repertoire is not a genetically determined one, but rather that the repertoire of T lymphocytes strongly depends on the postnatal selection process through the intrinsic idiotypic repertoire of B lymphocytes, i.e., internal images.     

Antigen-specific suppressor T lymphocytes (Leu-2a+3a-) in human schistosomiasis japonica

Immunoregulatory mechanisms in human schistosomiasis japonica were investigated through in vitro T lymphocyte-macrophage co-culture experiments. High responder T lymphocytes responded to the schistosomal adult worm antigen in the presence of HLA-DR-compatible low responder macrophages, whereas low responder T lymphocytes failed to respond to this antigen even in the presence of HLA-DR-compatible high responder macrophages. This observation strongly suggested that T lymphocytes, but not macrophages, controlled the low responsiveness to the schistosomal adult worm antigen. When high responder lymphocytes were challenged with the schistosomal antigen in the presence of low responder T lymphocytes, low responder T lymphocytes caused an antigen-specific suppression, in a dose-dependent manner, of the responsiveness of high responder lymphocytes. The suppressor T lymphocytes were mitomycin C resistant and were positive for Leu-2a, but were negative for Leu-3a. When Leu-2a+ T lymphocytes were depleted from low responder T lymphocytes, a vigorous response by the Leu-2a-depleted T lymphocytes (Leu-2a-3a+) to the schistosomal adult worm antigen was observed. By adding back the Leu-2a+ T lymphocytes into autologous T lymphocyte subpopulations, the specific response to the adult worm antigen was completely suppressed. These findings clearly demonstrate the existence of Leu-2a+3a- suppressor T lymphocytes that can control low responsiveness to the schistosomal adult worm antigen in man.     

Neutrophil recruitment and bacterial clearance correlated with LPS responsiveness in local gram-negative infection

The inflammatory response to Gram-negative infection was studied in LPS responder and nonresponder C3H mice. Twenty-four hours after ascending E. coli urinary tract infection, an influx of neutrophils into the urine was observed in C3H/HeN mice (Lpsn,Lpsn); no significant neutrophil influx occurred in C3H/HeJ mice (Lpsd,Lpsd) at this time. A second peak of urinary neutrophil excretion was observed in both strains of mice approximately 6 days post-infection. The first, but not the second peak was inducible by inoculation with formalin-killed E. coli but not by Gram-positive bacteria. This finding suggested that the first peak is triggered by LPS, whereas the second peak emanates from other bacterial components which activate both LPS responder and nonresponder mice. The first peak of the inflammatory response was inversely related to bacterial clearance. C3H/HeJ mice (Lpsd,Lpsd) retained about 2000-fold more E. coli in the kidneys than C3H/HeN mice (Lpsn,Lpsn). The infection persisted despite the late-occurring influx of neutrophils in C3H/HeJ mice. These results suggest that an inflammatory response to LPS is required for the elimination of a local Gram-negative infection.     

Alteration in lymphocyte recognition repertoire during aging: II. Changes in the expressed T-cell receptor repertoire in aged mice and the persistence of that change after transplantation to a new differentiative environment

Changes in the T-lymphocyte alloreceptor repertoire associated with aging by exploring the frequency of cytotoxic T-lymphocyte precursors (CTLp) available for activation by various major histocompatibility complex (MHC) haplotypes in mice of different ages have been investigated. There was no consistent pattern of change in CTLp frequencies. Thus, for instance, while the frequency of responder C57Bl/6 CTLp for ATH alloantigen decreased with age, the frequency for C3H alloantigen increased. There was no significant change in the overall frequency of splenic CTLp (assessed irrespective of antigen specificity). No evidence was found that CTL produced by activated CTLp of aged mice were less specific in their lytic capacity that CTL produced by CTLp of young mice. However, by assaying responder CTLp cultures at limiting dilution we obtained evidence that the “burst size” (mean lytic capacity per responder well assayed at limiting dilution) was diminished with age of the donor of the CTLp pool. Furthermore, we obtained evidence that the apparent affinity of CTL for their target antigen was consistently decreased when those effector cells were derived from a pool of CTLp of aged mice. All of these changes reflected in mature T cells derived from aged mice were already apparent in the bone marrow stem cell pool of aged individuals and were not due to environmental influences alone, as assessed by the phenotype of T cells derived from young or old bone marrow stem cells transplanted to young or aged recipient mice. A final study has examined evidence for more subtle changes in the T-cell alloreceptor repertoire, reflecting heterogeneity in young or aged mice in the recognition repertoire associated with a given antigenic specificity. By preparing F₁ anti (parent anti-F₁)-suppressor cells directed against CTL from young parental mice (a, b, c), or aged parental mice (x, y, z), we have explored the heterogeneity in the anti-C3H alloreceptor repertoire in individual young or aged C57Bl/6 mice. Suppression by immunized F₁ animals was assessed in tissue culture (inhibition of mixed lymphocyte culture (MLC) responses) or in vivo (inhibition of lethal GvHD induced by inoculation of parental lymphocytes into sublethally irradiated F₁ hybrid mice). Irrespective of the assay system used, the data suggests that the receptor repertoire of aged T lymphocytes uses recognition structures different from those of young individuals, and that there is less individual-to-individual variation in the receptor repertoire of aged mice than in young mice.     

The control of autoreactivity. I. Lack of autoreactivity in murine spleens is due to concomitant presence of suppressor and autocytotoxic lymphocytes.

To determine if autocytotoxic lymphocytes were naturally occurring in murine spleens, C57BL/6 spleen cells were fractionated on discontinuous BSA gradients. Autocytotoxicity was assessed in vitro (cytotoxicity of C57BL/6 fibroblasts) and in vivo (splenomegaly and popliteal node enlargement in C57BL/6 mice). A medium density subpopulation of lymphocytes was shown to be autocytotoxic and to be similar to autoreactive lymphocytes produced by the in vitro "sensitization" of splenic lymphocytes on syngeneic fibroblasts monolayers. The naturally occurring autocytotoxic lymphocytes express no detectable theta antigen, did not adhere to nylon, but did have an Fc receptor. In recombination experiments, BSA-fractionated lymphocytes were incubated with autocytotoxic and "sensitized" lymphocytes. A light density subpopulation was shown to suppress both autoreactive lymphocyte subpopulations at a 1:50 ratio. The suppressor cells were nylon nonadherent T lymphocytes. The lack of autoreactivity of unfractionated murine spleen cells is due to the concomitant presence of autocytotoxic and suppressor lymphocytes. If suppressor lymphocytes are selectively removed in vitro, the reactivity of autocytotoxic lymphocytes can be detected.     

Inability of mice to generate cytotoxic T lymphocytes to vesicular stomatitis virus restricted to H-2Kk or H-2Dk

H-2k mice are unable to generate cytotoxic T lymphocytes (CTL) to vesicular stomatitis virus (VSV). This apparent unresponsiveness is found for both major serotypes of VSV, VSV-Indiana and VSV-New Jersey. CTL unresponsiveness occurs despite the ability of H-2k mice to generate a humoral immune response against VSV that is comparable to that found in responder (H-2b and H-2a) strains. All H-2k mice regardless of background genes, including various Ig allotypes, were found to be nonresponders. H-2k-linked unresponsiveness mapped to both H-2Kk and H-2Dk and occurred despite the presence of responder alleles in (responder x nonresponder)F1 mice. The unresponsiveness cannot be attributed to an inability of VSV-infected H-2k target cells to express viral surface antigens of H-2 molecules. Further, unresponsiveness cannot be overcome by using secondary stimulation in vivo or in vitro. H-2k-linked unresponsiveness does not appear to be due to suppression, and no complementation has been found in various (nonresponder x nonresponder)F1 mice. Thus unresponsiveness to VSV in association with H-2Kk or H-2Dk appears to represent an extensive defect of immune responsiveness that probably occurs because VSV is not a natural mouse pathogen.     

The monoclonal antibody 41H16 detects the Leu 4 responder form of human Fc gamma RII.

Human FcR for IgG can be divided into three classes (Fc gamma RI, II, and III) based on their structure and reactivity with mAb. Fc gamma RII can be further subdivided into two categories based on functional and biochemical assays. These two Fc gamma RII subtypes were initially recognized by the failure of T cells from 40% of individuals to proliferate in response to mAb Leu 4 (mouse IgG1, anti-CD3), a response that requires the binding of the Fc region of the Leu 4 mAb to Fc gamma RII on monocyte accessory cells. Inas-much as mouse IgG1, does not bind efficiently to the nonresponder form of Fc gamma RII, mAb Leu 4 is unable to induce proliferation in these individuals. IEF data on Fc gamma RII from Leu 4 responder and nonresponder individuals suggested that the structural gene for Fc gamma RII consisted of two allelic forms R (responder) and N (nonresponder) producing the phenotypes RR, RN, and NN. Thus, exclusive expression of the nonresponder allele in monocytes of "nonresponder" individuals, appeared to be responsible for the lack of proliferation observed. In cooperation with the IVth International Conference on Human Leukocyte Differentiation Antigens, we analyzed CDw32 mAb to determine if they could distinguish the responder and nonresponder forms of Fc gamma RII. We report that mAb 41H16 binds preferentially to the responder allotypic form of Fc gamma RII expressed on human monocytes. When quantitative flow cytometry is used to measure the binding of both mAb 41H16 (responder Fc gamma RII) and mAb IV.3 (all myeloid cell Fc gamma RII), we are able to subdivide the responder population into homozygous and heterozygous responders. In addition, mAb 41H16 blocks the binding of mAb IV.3 to monocytes and inhibits proliferation when added to cells before addition of mAb Leu 4. We also show that polymorphonuclear leukocytes and platelets have the same allotypic differences in the binding of 41H16 as do monocytes. However, a subset of lymphocytes (previously shown to be B cells) expresses the 41H16 epitope with no evidence for donor to donor variability.     

T cell proliferative responses to a mitogen derived from Mycoplasma arthritidis are controlled by the accessory cell

Cell-free supernatants from broth cultures of Mycoplasma arthritidis (MAS) induce vigorous proliferative responses in thymus-derived T lymphocytes from H2k or H2d strains of mice. Populations of lymphoid cells from mice of H2b, H2q, or H2s haplotypes do not respond to this stimulus. Previous studies with lymphoid cells from congenic and recombinant strains of mice indicate that the T cell proliferative response induced by MAS is controlled by a gene(s) that maps to the I-E/C subregion of the murine major histocompatibility complex (MHC). The T cell proliferative response induced by MAS is dependent upon the presence of a population of la+, radioresistant accessory cells (AC). Data presented here demonstrates that responder strain AC that have been pulsed with MAS (followed by extensive washing) induced vigorous proliferative responses in subsequently added T cell populations. Pulsing of T cells with MAS, followed by the addition of AC, however, did not result in T cell proliferation. MAS was found to stimulate (responder X nonresponder) F1 T cells to proliferate if the MAS was presented in the context of either responder or (responder X nonresponder) F1 AC; nonresponder strain AC were ineffective in this regard. Nonresponder strain T cells were found to be capable of responding to MAS if it was presented in the context of responder strain AC, even if the T cells and AC were completely allogeneic. Thus, nonresponder strain T cells mounted vigorous proliferative responses if the MAS was presented in the context of responder strain AC. Conversely, responder strain T cells did not respond to MAS presented in the context of nonresponder strain AC. In addition, lymphoid cells from a B10 leads to B6AF1 radiation bone marrow chimera were also found to be capable of responding to MAS, but only in the presence of AC that expressed cell surface determinants controlled by the I-E/C subregion. The data presented here indicate that MAS-induced T cell proliferative responses are controlled at the level of the AC by a gene(s) that maps to the I-E/C subregion of the MHC.     

Genetic and biochemical evidence for the involvement of a bacterial component in the mitogenic properties of polyribonucleotides on murine B lymphocytes.

The mitogenic response of C3H/HeJ mice to the B cell mitogens, poly C and poly I, is approximately one-half the response measured in various LPS-responder strains. C3H/HeJ mice respond normally to poly I:C, the heteroduplex polymer. The low responder phenotype of C3H/HeJ mice to poly C and poly I is shown by an analysis of (C3H/HeJ x C57BL/6J-By-Ps)F1 X C3H/HeJ backcross progeny to result from a gene locus that is closely linked or identical to the defective LPS response locus expressed by the C3H/HeJ strain. The entire mitogenic activity in poly C preparations and most of the mitogenic activity in poly I preparations is insensitive to ribonuclease degradation. Hot aqueous phenol extraction of the polynucleotides separates the majority of the mitogenic activity that is soluble in the combined interface and phenol phase fraction from the aqueous soluble polynucleotides. The ribonuclease-insensitive, phenolsoluble contaminant elicits a reduced response in C3H/HeJ mice as compared to an LPS responder strain. We conclude that 1) poly C has no inherent mitogenic activity; 2) poly I preparations contain both ribonucleasesensitive and insensitive mitogenic activities; 3) the ribonuclease-resistant mitogenic activity in polynucleotide preparations has properties unlike those of LPS or lipid A; and 4) the product of LPS response gene has an effect upon the mitogenic stimulation of spleen cells by the contaminant.     

Immune recognition by cytotoxic T lymphocytes of minor histocompatibility antigens expressed on a murine colon carcinoma line

We have characterized in vivo and in vitro responses of mice to the BALB/c-derived carcinoma, C26. BALB/c mice were highly susceptible, in a dose-dependent fashion, to local tumor development following subcutaneous injection of C26. Other strains of mice, including allogeneic strains and major histocompatibility complex compatible strains of different minor histocompatibility (H) backgrounds, were resistant to C26-induced tumors. The basis for resistance of mice to C26 was studied using an in vitro-derived C26 line as target cells in microcytotoxicity assays, and as a source of antigen for in vivo priming. An H-2d-specific alloreactive cytotoxic T lymphocyte (CTL) line was isolated from C57BL/6 mice primed with C26, demonstrating the expression, and immune recognition, of MHC class I antigens on C26. C26 also expressed minor H antigens of BALB background as demonstrated by the ability of CTL specific for BALB minor H antigens to selectively lyse C26. Conversely, minor H antigens on C26 were immunogenic across a minor H barrier as demonstrated by the ability to raise anti-minor H CTL to C26 from minor H disparate strains. Collectively, those experiments indicate that C26 may be useful for immunologic and biochemical studies of murine minor H antigens, and for in vivo and in vitro studies of local immunity.     

Strain Differences in the Immunogenicity of Aggregated Human IgG and the Adjuvant Action of Lipopolysaccharide on the Low-Responder Strain of Mice

Strain differences in the antibody response to human IgG (HGG) were observed when aggregated HGG was injected intravenously. Lipopolysaccharide (LPS) administered subsequently markedly enhanced the antibody response to HGG in low responder C57BL/6 mice as compared with that in high responder DDD, C3H/He or (C57BL/6 × DDD)F₁ mice. Aggregate-free preparation of HGG at a dose of 0.5 mg induced immunological tolerance in all strains of mice tested. LPS injected subsequently converted tolerogenic, aggregate-free HGG into immunogen in DDD mice but not in C57BL/6 mice. To determine the correlation between adjuvanticity and mitogenicity of LPS, spleen cells from normal mice were cultured in the presence of LPS and ³H-thymidine uptake was measured. Spleen cells of DDD mice incorporated three times as much ³H-thymidine as those of C57BL/6 mice. There seems no strong correlation between both activities of LPS. The data obtained are discussed in terms of strain differences in the macrophage function for processing the antigen.     

Immune response to the p-azobenzenearsonate (ABA)-GAT conjugate. II. Hapten-specific T cells induced with ABA-GAT in GAT responder X nonresponder F1 hybrids are restricted to the nonresponder haplotype

Immunization of mice with the ABA-GAT conjugate stimulates GAT-specific T helper cells in GAT-responder animals and ABA-specific helpers in nonresponders. Unexpectedly, immunization of (responder X nonresponder) F1 mice, which have the GAT-responder phenotype, leads to the recruitment of both ABA- and GAT-specific clones of T helper lymphocytes. The GAT-reactive population is restricted to the haplotype of the responder parent (Iak), whereas ABA-specific T cells are mostly restricted to the nonresponder one (Ias). This is demonstrated by the ability of monoclonal antibodies to parental la antigens to inhibit T cell proliferation to GAT or ABA-Tyr in vitro. Consistently, ABA-GAT-primed F1 T cells can only activate nonresponder B cells to proliferate in the presence of ABA-Tyr and responder B lymphocytes in the presence of GAT. Furthermore, F1 T cells seem to recognize both ABA and GAT epitopes only in association with molecules encoded by the I-A subregion. Analysis of ABA-specific F1 T cell lines generated by in vitro stimulation with ABA-Tyr or ABA-GAT demonstrates a competition between GAT- and ABA-specific T cells present in the hybrid T cell repertoire and restricted to the same parental I-Ak molecule. The results indicate that F1 macrophages can present both ABA and GAT epitopes to T cells in association with the two parental and hybrid Ia determinants. It seems unlikely that the absence of GAT-specific T cells restricted to the nonresponder I-A in the F1 is due to suppressor T cells. Thus, the competition model that we propose, to explain the selective F1 T cell response to ABA-GAT, leads us to believe that GAT nonresponder animals may lack clones capable of recognizing, with a high affinity, I-As + GAT.     

Characterization and genetic control of the immune response to synthetic polypeptide antigens of defined geometry.

Both humoral and cell-mediated immune responses to the synthetic helical hapten-carrier conjugate poly-Glu-Tyr-Lys(TNP)-(Glu-Tyr-Ala)5 were found to be linked to the major histocompatibility locus in mice and guinea pigs. The responder mouse strains (H-2d haplotype) showed a primary IgM response with an IgG component appearing after the secondary immunization. The antibody response was accompanied by a positive DTH reaction in responder strains. Nonresponder mice (H-2b or H-2k haplotypes) showed neither IgM nor IgG antibodies and the DTH reaction was negative. Administration of the antigen as a complex with an immunogenic carrier was not effective in inducing a response in nonresponder mice. In guinea pig studies, it was found that strain 2 animals were able to mount an antibody response against the TNP-hapten and a DTH response against the polypeptide backbone. Strain 13 animals gave no anti-TNP antibodies at the lower dose levels and DTH activity was entirely negative for all doses of immunizing antigen. Replacement of the TNP hapten by the arsanilazo dipeptide derivative, BOC-gly-ARA-tyrosine, converted the nonresponder strain 13 guinea pigs into complete responders showing antibody and DTH reactions to both the hapten and the polypeptide backbone.     

Strain variation in BCG-induced chronic pulmonary inflammation in mice. I. Basic model and possible genetic control by non-H-2 genes.

C57BL/6 mice (haplotype H-2b) responded in a dose-dependent fashion to killed BCG by marked enlargement of the spleen and lung. Neither CBA nor C3H mice (haplotype H-2k) responded to such treatment. Pulmonary inflammation in responder B6 animals was characterized by a marked chronic interstitial and alveolar granulomatous process, and was accompanied by occasional granulomata, hyperemia, and loss of architecture in the spleen. Inflammation in non-responder CBA and C3H animals was minimal in both the lung and spleen. The response does not appear to be controlled by genes within the major histocompatibility complex, but is associated with a C57 background. B10.BR mice (responder background, H-2k) were responder animals and C3H.SW mice (nonresponder background, H-2b) were nonresponders. In addition, all animals tested with a C57 background were responders even though two of these strains were not H-2b (C57BL/Ks, H-2d and C57Br/cd, H-2k). The resolution of the mechanism of genetic control of this response in mice may provide information relevant to possible genetic control of chronic pulmonary inflammation in man.