Genetic control of T-cell proliferative responses to poly(glu40ala60) and poly(glu51lys34tyr15): Subregion-specific inhibition of the responses with monoclonal Ia antibodies

The relationship betweenIr genes and Ia antigens was studied in the T-cell proliferative responses to two synthetic polypeptides poly(glu⁴⁰ala⁶⁰) (GA) and poly(glu⁵¹lys³⁴tyr¹⁵) (GLT¹⁵). The response to GA was found to be controlled by anIr gene in theI-A subregion, whereas the anti-GLT¹⁵ response was shown to be under dual control, oneIr gene mapping probably in theI-A subregion, and the other in theI-E subregion. We obtained two different lines of evidence suggesting identity ofIr and Ia genes. First, the presence of certain serologically identified allelic forms of the I-A-encoded A molecule correlated with the responder status to GA both in inbred strains and in B10.W lines, the latter carrying wild-derivedH-2 haplotypes. Thus the Ir and Ia phenotypes were not separable in strains of independent origin. Second, the anti-GA response was completely inhibited by monoclonal antibodies against determinants on the A molecule (Ia.8, 15, and 19), but not by a monoclonal antibody against a determinant on the E molecule (Ia.7). In contrast, the anti-GLT¹⁵ response was only inhibited by a monoclonal antibody against the E molecule, but not by antibodies against the A molecule. Our data support the hypothesis that Ia antigens, as restriction elements for T-cell recognition, may in fact be the phenotypic manifestation ofIr genes.     

Unigenic and multigenicI region control of the immune responses of mice to the GAT10 and GLΦ-GLT terpolymers

Recombinant strains of mice with known alleles in theI region of theH-2 complex were used to map theH-2 linked immune response genes controlling responsiveness to random terpolymers GAT¹⁰ and GL. TheIr-GAT gene was mapped to either theIA orIB subregions. In contrast, data obtained in the GL-GLT system indicated multigenic control. The responsiveness of the B10.A(3R), B10.A(5R), and B10.S(9R) recombinants indicated that one immune response gene,IrGL-GLT _A, mapped to the right ofIB, i.e., in theIC subregion. The nonresponsiveness of the B10.A(1R), B10.A(2R), B10.M(17R), and AQR mice having responderIC ^d alleles butIA ^k-IB ^k nonresponder alleles and the positive response of a (C57BL/6 × A/J)F₁ hybrid derived from two nonresponder parental strains indicated the presence of a second gene inIA-IB subregions,Ir-GL-GLT _B. The interaction between these two genes, each present in a differentI subregion, controls the immune response.     

T(Iat)- and B(Iab)-cell alloantigens determined by theH-2 linkedI region in mice

The specificity of an antiserum directed againstI region associated (Ia) antigens is described. The serum was raised in (DBA/1×B10.D2)F₁ mice against lymphocytes of AQR mice, differing from the responder for theI region only. The serum reacts with Ia antigens expressed on B cells (Iab) as well as with Ia antigens expressed on T cells (Iat). Absorption studies indicate that B cells possess at least two Ia antigens, and one of these is shared by T cells. However, this shared antigen is not present on the surface of lymphocytes of thymectomized mice. Analysis of the strain distribution of Iab and Iat antigens revealed that the Iab antigens are present on lymphocytes of mice carrying theIA ^k subregion and that the Iat antigens are present on lymphocytes of mice carryingI region genes of theH-2 ^k haplotype located between theIA andIB subregions. This conclusion is based on the analysis of the antiserum's reactivity with T and B cells of the strains B10.A(2R), B10.A(4R) and B10.HTT: the serum reacts with B and T cells of B10.A(2R) but only with B cells of B10.A(4R) mice and only weakly with T cells of B10.HTT mice.Abbreviations ALG antimouse lymphocyte globulin from rabbits - B cells bone marrow derived lymphocytes - B10 C57BL/10Sn mice - D1D2F₁ (DBA/1×B10.D2)F₁ hybrid mice - GVHR graft-vs-host reaction - Ia I region associated antigen - Iab on B cells - Iat on T cells - MLR mixed lymphocyte reaction - T cells thymus-derived lymphocytes - Thy-1 thymus antigen 1, formerly called theta - Tx-Lyc lymphocytes of thymectomized, ALG treated, lethally irradiated and anti-Thy-1 treated bone marrow reconstituted mice - 2R B10.A(2R)/SgSn mice - 4R B10.A(4R) mice     

Molecular events in the processing of avidin by antigen-presenting cells (APC)

The immune response of T lymphocytes to avidin was measured by proliferative assays, antibody production and delayed-type hypersensitivity. Mice ofH-2 ^k haplotypes were found to be low responders, whereas mice of other haplotypes, and particularly ofH-2 ^s , were high responders.Ir genes controlling this response were mapped to theI subregion ofH-2. Helper T cells were found to be responsible for the Ir phenotype of antibody production. These results indicate the feasibility of using the avidin-biotin complex as a tool for studying molecular mechanisms by which antigens underIr gene control are processed and presented to T lymphocytes.Abbreviations used in this paper Ir genes, immune-response genes - H-2 murine major histocompatibility complex - APC antigen-presenting cell - OA ovalbumin - BSA bovine serum albumin - DNP dinitrophenyl - DNP-OA DNP-ovalbumin - DNP-Av DNP-avidin - DNP-BSA DNP-bovine serum albumin - CFA complete Freund's adjuvant - PPD purified protein derivative - PBS phosphatebuffered saline - IP intraperitoneal - LNC lymph-node cells - DTH delayed-type hypersensitivity     

The T-Cell factor specific for poly(Tyr,Glu)-Poly(Pro)-Poly(Lys) is an I-Region gene product

The nature of a T-cell factor specific for poly(Tyr,Glu)-poly(Pro)-poly(Lys) [(T,G)-pro-L] was established in the present study. The activity of the (T,G)-Pro-L-specific factor was not removed by anti-mouse immunoglobulin Sepharose columns, suggesting that it is not a classical immunoglobulin. On the other hand, the factor lost its activity after passage through immunoadsorbents prepared with anti-H-2 sera raised against theH-2 haplotypes of the mouse strains in which the factor was prepared. Furthermore, this factor was adsorbed byI region-specific antisera but not by antisera directed against theI-J andI-C subregions as well as theK andD regions of theH-2 complex. Thus, the (T,G)-Pro-L-specific T-cell factor is most probably anI-A subregion gene product.     

Characterization of a newIr-GLT gene and its location in theI-region of theH-2 complex

The data presented in this paper characterize the immune responses in mice to the two related random terpolymers, poly(Glu⁵⁷Lys³⁸Tyr⁵) (GLT⁵) and poly (Glu⁵⁵Lys³⁴Tyr¹⁵) (GLT¹⁵), which are similar to the previously reported response against the terpolymer poly(Glu⁵⁸Lys³⁸Phe⁴) (GLØ). Responsiveness is linked to theH-2 ^d ,H-2 ^ja ,H-2 ^q andH-2 ^r haplotypes. The observed responsiveness of the recombinant strain B10.A(5R)tentatively maps theIr-GLT gene to the right of theIB subregion, i. e., in theIC subregion which codes for lymphocyte alloantigens. If confirmed this would be the firstIr gene to be mapped in theIC subregion.     

Regulation of T15 idiotype dominance. II. Genes unlinked to the Igh locus regulate T15 dominance of the secondary adoptive transfer response to phosphocholine

We have studied the idiotype and fine specificity of the secondary immune response to phosphocholine (PC) in C57BL (B10, B10.D2, and B.C8) and BALB (BALB/c, BAB-14, and C.B20) congenic strains of mice. In vivo IgM responses of mice from these two genetic backgrounds differed in their T15 idiotypic representation. BALB strains expressed the T15 idiotype on greater than 90% of their IgM, PC-specific plaque-forming cells (PFC), whereas C57BL strains expressed the T15 idiotype on approximately 50% of their IgM PFC. All strains examined expressed greater than 75% PC-inhibitable, VHPC idiotype-positive, IgM PFC. The IgG3 and IgA memory responses were similar to the IgM memory response; BALB strains produced a higher proportion of T15+ PFC than C57BL strains; however, the majority of IgG3 and IgA PFC in all strains were VHPC+, and PC-inhibitable. In contrast, the IgG1 memory response was not dominated by T15+, VHPC+, PC-inhibitable PFC in any of the strains tested. The IgG1 PFC required nitrophenylphosphocholine (NPPC) for efficient inhibition. The IgG2 memory response generally mimicked the IgG1 response with respect to idiotype and specificity. These data demonstrate that the representation of the T15 idiotype in the anti-PC immune response is determined by genes outside both the MHC and Igh genetic loci. Control of T15 expression in secondary IgM, IgG3, and IgA anti-PC responses was examined by using a cell-mixing protocol with primed T and B cells from BALB/c and B10.D2 mice. T15 representation in these responses was determined by the genotype of the B cell, not by the genotype of the helper T cell. Similarly, the B cell genotype was responsible for the idiotypic profile of a primary, in vitro, T-dependent, anti-PC response.     

Two distinct high immune response phenotypes are both controlled byH-2 genes mapping inK orI-A

Murine responses to immunization with 2, 4, 6-trinitrophenyl (TNP) conjugated to autogenous mouse serum albumin (MSA) in complete Freund's adjuvant (CFA) are controlled by a gene(s) in theK orI-A region of theH-2 complex. High immune responses of bothH-2 ^d andH-2 ^b mice have been mapped to this region of the major histocompatibility complex. No modifying effects were observed from genes to the right ofI-A in either responder haplotype. High responsiveness controlled byK ^b orI-A ^b is inherited with complete or partial recessivity, depending on the route of immunization and the sex of the responder. However, high responsiveness controlled byK ^d orI-A ^d is inherited dominantly. This unusual pattern of inheritance of immune responsiveness to TNP-MSA is consistent with the genetic mapping toK orI-A. TNP-MSA-specific T-cell reactivity following immunization with TNP-MSA in vivo was examined utilizing a T-cell-dependent proliferation assay in vitro with cells obtained from high or low responder mice. Genetic mapping and mode of inheritance in this assay for antigen-specific T-cell reactivity corresponded with results obtained from a plaque-forming cell (PFC) assay measuring antibody production by B cells. Both the proliferative and PFC responses are probably under the sameIr gene control. Both gene dosage effects and Ir-gene-product interaction could influence the generation of specific immune responsiveness in F₁ hybrids between high and low responders to TNP-MSA.     

I-A Mutation resulted in a selective loss of an antigen-specific Ir gene function

The immune responses to several antigens were compared in the I-A mutant mouse strain B6.C-H-2^bm12 and the wild-type strain C57BL/6. With a lymph node cell proliferation assay, the response to two of these antigens, beef insulin and (TG)A-L, was demonstrated to be controlled by a gene in the I-A^b region. B6.C-H-2^bm12 mice failed to respond to beef insulin, while their responses to (TG)A-L, DNP-OVA and PPD were comparable with those of the wild-type strain C57BL/6. Taken together with previous studies, these data suggest that the product of a single pleiotropic I-A gene, an la molecule, functions as a histocompatibility, la, and MLR antigen, as well as a necessary component for Ir gene function. Furthermore, the data reported here demonstrate that la molecules have multiple functional “Ir determinants,” one of which has been altered in the B6.C-H-2^bm12 mutant. The B6.C-H-2^bm12 mice, therefore, represent a powerful analytical tool for the understanding of the cellular and molecular basis for Ir gene control of the immune response.     

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.     

Ia Restriction Specificity of KLH-Specific T Cells from Allogeneic Bone Marrow Chimeras Is Influenced by Histocompatibility at the H-2 and Minor Histocompatibility Loci

Ia restriction specificity involved in T cell proliferative responses to keyhole limpet hemocyanin (KLH) has been analyzed using a variety of allogeneic bone marrow chimeras. The chimeric mice were prepared by reconstituting irradiated AKR, SJL, B10.BR and B10.A(4R) mice with bone marrow cells from B10 mice. When such chimeric mice had first been primed with KLH in complete Freund's adjuvant (CFA), T cells from H-2 incompatible fully allogeneic chimeras showed significantly higher responses to KLH in the presence of antigen-presenting cells (APC) of donor strain (B10) than APC of recipient strain. However, in H-2 subregion compatible chimeras, [B10→B10.A(4R)], which were matched at the H-2D locus and at minor histocompatible loci, the T cells could mount vigorous responses to KLH with antigen-presenting cells (APC) of either donor or recipient type. The same results were obtained as well with chimeras that had been thymectomized after full reconstitution of lymphoid tissues by donor-derived cells. A considerable proportion of KLH-specific T cell hybridomas established from [B10→B10.A(4R)] chimeras exhibited both I-A^b and I-A^k restriction specificities. The present findings indicate that the bias to donor Ia type of antigen specific T cells is determined by donor-derived APC present in the extrathymic environment but that cross-reactivity to the recipient Ia is influenced to some degree by histocompatibility between donor and recipient mice, even though the histocompatible H-2D locus and minor histocompatibility loci seem not to be directly involved in the I-A restricted responses studied herein.     

Anti-Ia inhibits the activity of B cells but not a T cell-derived helper mediator

The effects of addition of anti-Ia sera to cultures of B cells responding to a number of different stimuli were studied. Anti-Ia sera inhibited the responses of B cells to thymus-dependent and thymus-independent antigens. The effects of antisera directed at different subregions within theI region were examined, using the same anti-Ia serum and mouse strains congenic atI. There was some indication that antisera directed at theI-C region might be more efficient at inhibiting responses to a thymus-independent antigen than to a thymus-dependent antigen. An antiserum to another B-cell surface component controlled by theH-2 complex, the D glycoprotein, had no effect on the response of B cells to a thymus-dependent antigen. By contrast, anti-Ia serum added to cultures had no effect on the activity of a T cell-derived, nonspecific, B-cell helper mediator (NSM). We concluded that the binding of anti-Ia sera to B-cell surfaces inhibited B-cell responses to antigen, either by competing directly with the binding of signal molecules, or by delivering an inhibitory signal to the B cell, such that it was subsequently refractory to stimulatory signals.     

Genetic control of the murine immune response to cholera toxin

This study was undertaken to determine whether previously noted differences in the immune response of inbred strains of mice to cholera toxin (CT) might be under immune response gene control. A series of inbred, congenic, and intra-H-2I region recombinant mouse strains were tested for responsiveness to CT after i.p. immunization with 0.1 micrograms CT in alum. Samples of plasma were collected at intervals before and after priming and boosting. IgG and IgA anti-CT were measured by ELISA. In three different sets of congenic strains, the level of IgG anti-CT clearly depended on the H-2 haplotype of the strain rather than on any background or Igh genes. Strains with the H-2b and H-2q haplotypes were high responders, and strains with the H-2k, H-2s and H-2d haplotypes were low responders. Within the H-2 complex, the IgG anti-CT response was mapped to the I-A subregion with the use of congenic intra-H-2I region recombinant strains. In contrast to these results with IgG anti-CT, plasma IgA anti-CT levels were uniformly low and indeterminate. We conclude that the murine IgG anti-CT response is controlled by a locus within the I-A subregion of H-2--a remarkable finding, considering the known abilities of this toxin to bind to and to directly stimulate lymphocytes.     

H-2-linked recessiveIr gene regulation of high antibody responsiveness to TNP hapten conjugated to autogenous albumin

The antibody response to the hapten 2,4,6-trinitrophenyl (TNP) conjugated to autogenous mouse serum albumin (MSA) is regulated by anIr gene(s) located within the major histocompatibility complex (MHC). Both the qualitative and quantitative ability of congenic strains to produce TNP-specific antibodies are functions of theH-2 haplotype. Thus, mouse strains may be classified as high (H-2 ^d), intermediate (H-2 ^b,H-2 ^s), and low responders (H-2 ^a,H-2 ^k,H-2 ⁿ,H-2 ^p,H-2 ^q). Antibody responses, as measured by antigen-binding capacities in modified Farr assays, were compared among strains carrying recombinantH-2 haplotypes and their hybrid progenies. Distinct high- and low-responder phenotypes were evident throughout the time course of both primary and secondary antibody responses. The gene locus controlling specific responsiveness to TNP-MSA, now designatedIr-6, was mapped within theI-B subregion of theH-2 complex. Recessive inheritance of high responsiveness was confirmed in hybrid progenies of three different low × high-responder crosses.     

Experimental allergic orchitis in mice. VI. Recombinations within the H-2S/H-2D interval define the map position of the H-2-associated locus controlling disease susceptibility

Susceptibility to autoimmune orchitis is associated with an immune response (Ir) gene (now designated Orch-1) which was preliminarily shown to reside at or near the H-2D subregion of the major histocompatibility complex in the mouse (H-2). In this study, the role of H-2 in controlling both disease susceptibility and the phenotypic expression of infertility associated with autoimmune orchitis has been significantly extended. Of nine C57BL/10SnJ and three BALB/cAnN H-2 congenic strains, only those mice possessing the H-2 ^d, H-2 ^p haplotypes exhibited autoimmune orchitis accompanied by infertility. All other congenic strains, including those expressing the H-2 haplotypes v, q, b, s, r, f, and k were of the low responder phenotype. In addition, disease susceptibility was found to be inherited as a dominant trait in H-2 congenic F₁ hybrid mice. In order to map the precise location of the Orch-1 locus within H-2, 32 intra-H-2 recombinant congenic strains possessing defined crossovers in various locations throughout the H-2 region were studied. The results of the analysis indicate that Orch-1 maps within the interval between the H-2S and H-2D regions. Our results also indicate that class II genes, i.e., A and E region-encoded genes, have little discernable effect in controlling disease susceptibility and resistance despite the fact that testicular lesions can be adoptively transferred with Ia-restricted CD4⁺ effector T cells. A comparison of the Orch-1 alleles with the genotypes of two additional markers which map within the H-2S/H-2D interval suggests the following gene order: H-2S--TNP-Ficoll--Orch-1--Tnfa--H-2D. Address correspondence and offprint requests to: C. Teuscher.     

A locus affecting immunoglobulin isotype selection (Igis1) maps to the MHC region in C57BL, BALB/c and NOD mice

We have previously shown that H2b mice with B10 or BALB genetic backgrounds have higher basal levels of IgG2a than H2k and H2d congenic strains and, hence, have low IgG1/IgG2a ratios, which is consistent with a T1 cytokine milieu. The phenotypic marker of the high IgG2a levels, denoted immunoglobulin isotype-1 (Igis1) was provisionally mapped telomeric of IEbeta using MHC recombinant mice. In addition, data from B10.A(2R), B10.A(1R) and B10.A(18R) mice indicated that Igis1 may lie in a 27 kb region between G7b (Sm-X5) and G7c. In the present study we confirm that Igis1 is in the H2 region using BALB and B10 congenic F2 mice. H2bb F2 mice had higher IgG2a levels than the H2dd parental strains. H2bd F1 and F2 mice on the B10 background produced IgG2a levels comparable with the H2bb parental strain, indicating that the b allele was dominant. In contrast, the H2bd F1 and F2 mice on the BALB background produced IgG2a levels between those of the H2bb and H2dd parental strains, indicating codominance of the b and d alleles. This suggests that a background gene influences regulation of IgG2a levels by Igis1. Non-obese diabetic (NOD) mice (KdIAg7IEnu11Db), which can develop type 1 diabetes, had higher levels of IgG2a than NOD-H2d congenic mice. Thus, Igis1 affects isotype selection in the presence of non-MHC diabetes genes. As type 1 diabetes is associated with T1 responses, Igis1 may affect susceptibility to this condition.     

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.     

H-2 effects on cell-cell interactions in the response to single non-H-2 alloantigens

Immune response (Ir) genes mapping in theI region of the mouseH-2 complex appear to regulate specifically the presentation of a number of antigens by macrophages to proliferating T cells. We have investigated the possibility that similarIr genes mapping in theH-2K andH-2D regions specifically regulate the presentation of target antigens to cytotoxic effector T cells. We report that the susceptibility of targets expressing specific non-H-2 H alloantigens to lysis by H-2-compatible, H-antigen-specific cytotoxic effector T cells is controlled by polymorphicH-2K/D genes. This control of susceptibility to lysis is accomplished through what we have defined operationally as antigen-specific regulation of non-H-2 H antigen immunogenicity. High immunogenicity of the H-4.2 alloantigen is determined by a gene mapping in theH-2K region ofH-2 ^b . However, high immunogenicity of H-7.1 is determined by a gene mapping in theH-2D region ofH-2 ^b . High immunogenicity of the H-3.1 alloantigen is determined by genes mapping in both theH-2K andH-2D regions ofH-2 ^b . Therefore, genes mapping in theH-2K andH-2D regions serve a function in presenting antigen to cytotoxic effector T cells. This function is analogous to that played byI-regionIr genes expressed in macrophages which present antigen to proliferating T cells. We present arguments for classification of theseH-2K/D genes as a second system ofIr genes and discuss the implications of twoH-2-linkedIr-gene systems, their possible functions, and their evolution.     

I-Region genetic restrictions imposed upon the recognition of KLH by murine T-cell clones

Data presented in this paper show that the recognition of keyhole limpet hemocyanin by murine T-cell clones is restricted by products of the I region. These data have been obtained by genetic mapping studies as well as by the use of monoclonal la-specific antibodies which inhibit the ability of antigen-presenting cells to effectively present antigen to such T-cell clones. Use of heterozygous antigen-presenting cells derived from crosses between B6.C-H-2 ^bm12 and B10.A(4R) mice have allowed us to show that both trans-complementing I-A products are used for restriction of recognition of KLH. These data were confirmed using monoclonal Ia antibodies to inhibition recognition of KLH by the same T-cell clones. Thus, we have shown that there exist hybrid molecules formed by free combinatorial association of products encoded within the I-A subregion which restrict the recognition of soluble antigen. Additionally, we have shown that the molecule formed by complementation between the alpha chain encoded within the I-E region and a beta chain encoded within the A region (A_e) can function effectively in presenting KLH to certain murine T-cell clones. These results support the hypothesis that the recognition of individual antigenic epitopes within large multideterminant antigens is under the control of Ir genes.     

Murine responses to (Tyr-Glu-Ala-Gly)n

A series of known sequential polypeptides is being synthesized and used in our laboratory to study the contribution of antigen structure, i. e., amino acid sequence and conformation in antigen recognition and specificity of the immune response. The capacity to respond to one such -helical polypeptide (T-G-A-Gly)_n, is T-cell dependent and restricted to mice of theH- 2^b haplotype. The response is controlled by anIr gene mapping to theK region and/or theIA subregion which allows the animal to make both a T-cell mediated response, as well as a humoral response to the polypeptide. The response of three mutant strains at theK end of the major histocompatibility locus (MHC) need not differ from that of the responder parental haplotype.PETLES obtained from mice possessing a responder haplotype proliferate when cultured in vitro with (T-G-A-Gly)_n. The antibody level of individual inbred mice of a given strain at a given time differs significantly (from 80% binding to less than 10% antigen bound in 3 out of 57 mice). There is also great individual variability in time of appearance of the antibody response and where peak optimal levels are seen. Possible explanations for the variation in the antibody expression include: (a) the polymer is a weak immunogen, (b) the presence of modifier gene(s) outside of the major histocompatibility complex controlling the magnitude of the antibody level, (c) the possible effect of the polymer which is a B cell mitogen as a generator of suppressor T cells and, (d) a feedback mechanism effect on B cells controlling the antibody level.This work was supported in part by the following grants: The National Institute of Allergy and Infectious Diseases A107825; American Cancer Society Grant IM-5F; National Foundation-March of Dimes 1-492.