IL-1 receptor signaling is required at multiple stages of sensitization and elicitation of the contact hypersensitivity response

Contact hypersensitivity (CHS) is a CD8 T cell-mediated response to hapten skin sensitization and challenge. The points at which IL-1R signaling is required during this complex, multistep immune response have not been clearly delineated. The role of IL-1R signaling during 2, 4 dinitro-1-fluorobenezene (DNFB) sensitization to induce hapten-specific CD8 effector T cells and in the trafficking of the effector T cells to the DNFB challenge site to elicit the response were investigated using IL-1R deficient mice. DNFB-sensitized IL-1R(-/-) mice had low CHS responses to hapten challenge that were caused in part by marked decreases in hapten-specific CD8 T cell development to IL-17- and IFN-γ-producing cells during sensitization. Hapten-primed wild type CD8 T cell transfer to naive IL-1R(-/-) mice did not result in T cell activation in response to hapten challenge, indicating a need for IL-1R signaling for the localization or activation, or both, of the CD8 T cells at the challenge site. Decreased CD8 T cell priming in sensitized IL-1R(-/-) mice was associated with marked decreases in hapten-presenting dendritic cell migration from the sensitized skin to draining lymph nodes. Transfer of hapten-presenting dendritic cells from wild type donors to naive IL-1R(-/-) mice resulted in decreased numbers of the dendritic cells in the draining lymph nodes and decreased priming of hapten-specific CD8 T cells compared with dendritic cell transfer to naive wild type recipients. These results indicate that IL-1R signaling is required at multiple steps during the course of sensitization and challenge to elicit CHS.     

Mechanisms involved in the antibody-mediated suppression of tuberculin-type delayed hypersensitivity: II. The sensitivity of tolerance induction to cyclophosphamide pretreatment and splenectomy,and the demonstration of active suppression

The induction of tuberculin-type delayed hypersensitivity, as measured by skin test, can be specifically inhibited by administration of antibody during sensitization. The cellular mechanisms involved in this tolerance were investigated in CAP₁ mice, using chicken conalbumin as antigen. Tolerance was prevented when mice were treated with Cyclophosphamide 2 days before sensitization and suppression. However, it was not affected by splenectomy 7 or 21 days before sensitization. This tolerance could be transferred to normal CAF₁ mice with spleen cells, but not with thymocytes, when taken from donor mice 21 to 28 days after sensitization and tolerance induction. Production of these cells in the donors required both antibody and antigen. The cells responsible for the transfer were B cells, as shown by their sensitivity to rabbit anti-mouse-immunoglobulin serum and complement. In addition to B cells, serum from tolerant mice also could transfer suppression at 21 to 28 days. We conclude that sensitizing mice, and treating them with specific immunosuppressive antiserum, induces the recipients to make suppressor B cells and suppressive humoral factors, which are involved in arresting the induction of tuberculin-type delayed hypersensitivity.     

A requirement for helper T cells in the induction of delayed-type hypersensitivity

This paper describes a model system for studying the role of helper T cells in the induction of delayed-type hypersensitivity (DTH). Cyclophosphamide- (CP) treated mice sensitized with antigen 3 days later develop high levels of delayed-type immunity; however, DTH cannot be demonstrated in mice that are sensitized with antigen 1 day after drug treatment. The inability to respond to antigen 1 day after CP treatment can be restored if either normal or low-dose primed spleen cells are transferred at the time of sensitization. Although irradiated (1500 rad) normal spleen cells are unable to restore DTH, such treatment has no effect on the primed spleen cell population. The lymphocytes responsible for restoring the DTH response were identified as T cells, in that treatment with anti-Thy-1.2 serum and C abrogated their effect. Furthermore, restoration of the DTH response was dependent on the presence of antigen at the time of lymphocyte transfer; irradiated primed cells could not transfer DTH alone. The DTH effector cells in reconstituted mice were identified as originating from the host and not from the transferred cell population. This was accomplished by using anti-H-2 serum to identify the source of the DTH effector cells after transferring parental (H-2b) irradiated primed spleen cells into CP-treated F1 mice (H-2b,k). Thus, the irradiated transferred cells are behaving as helper T cells and promoting the development of DTH effector cells in the host.     

Ir gene-controlled response to haptenated hen ovomucoid: isotypic specificity and dominant nonresponsiveness

We have examined the isotypic pattern of the response of mice to the Ir gene-controlled antigen, dinitrophenyl-ovomucoid (DNP-OM). H-2 kappa mice are high responders (HR); (H-2b,d mice are low responders (LR). The isotype patterns of HR and LR strains differ both quantitatively and qualitatively. In the primary response to doses of 20-100 micrograms DNP-OM, HR strains produce IgM and IgG antibodies, whereas LR strains produce only IgM. Background genes modify the kinetics of the IgGl primary response in HR strains, but no background was found which allowed an IgG response in a LR strain. In secondary responses, priming with 0.2 microgram DNP-OM increases secondary responses in HR strains, and decreases them in LR strains. Control of this response maps to I-A, and is not altered by the bm 12 I-Ab mutation. The LR phenotype is dominant in (HR X LR)F1 mice.     

Regulation of the intensity of delayed-type hypersensitivity to sheep erythrocytes by the K-region of the major histocompatibility complex in mice

The injection of 6 x 10(9) sheep red blood cells (SRBC) to mice suppressed the delayed type hypersensitivity (DTH) in situ and activated spleen T cells which prevent sensitization of syngeneic recipients. Similar effect was obtained when suppressor cells induced in F1 hybrids were transferred to parental mice. Suppression was also reached in allogeneic strain combination if suppressor cells of donors and recipients shared the major histocompatibility complex (MHC). Studied performed with recombinant and mutant strains revealed that the prerequisite for interaction of DTH suppressors and effectors was the identity of K-region of MHC. Passive transfer of DTH to SRBC was also possible if donors and recipients were identical in K-region of MHC. It is believed that interaction between DTH suppressors and effectors is restricted by a region of MHC whose product takes part in antigen representation.     

The characterization of the delayed-type hypersensitivity reaction to H-Y antigens

We have evaluated the ability of certain inbred strains of mice to develop a delayed-type hypersensitivity response to the male H-Y antigen. It was found that C57BL/10, B10.GD and B10.A(5R) female mice responded to syngeneic male cells. B10.A(4R) females also responded to B10.A(4R) male cells although the reactivity was somewhat slighter. B10.A(2R), B10.D2 and BALB/c female mice could not respond to immunization with syngeneic male cells. The response was male-antigen specific and transferable by thymus-derived cells. Moreover, suggestive evidence of representation of H-Y was obtained, based on the ability of responder strains immunized with syngeneic cells to react to nonresponder male cells upon challenge.     

Type II collagen-induced murine arthritis: induction of arthritis depends on antigen-presenting cell function as well as susceptibility of host to an anticollagen immune response.

Two sets of ((resistant x susceptible) F1----parent) and (parent----F1) chimeric mice were prepared. In the chimeric combinations involving BALB/c and DBA/1 mice, all (F1----F1) chimeras developed arthritis as well as potent anticollagen responses after immunization with collagen, whereas all (F1----BALB/c) and (BALB/c----F1) chimeras induced neither arthritis nor immune responses. This type of F1 T cells could be activated with APC from DBA/1 but not from BALB/c mice. Thus, the failure of the [F1 in equilibrium with BALB/c] chimeras to mount anticollagen responses was due to a defect at the APC level. Another arthritis-resistant strain, C57BL/6, exhibited adequate APC function, but reduced T cell responsiveness, representing an intermediate responder. In the chimeric combinations involving C57BL/6 and DBA/1 mice, (F1----F1) and (C57BL/6----C57BL/6) chimeras developed very high and very low incidence of arthritis, respectively. (C57BL/6----F1) chimeras developed an appreciable incidence of arthritis under conditions in which this group of chimeras generated intermediate levels of anticollagen responses. In contrast, (F1----C57BL/6) chimeras developed low incidence of disease despite induction of strong responses. Moreover, cells from collagen-immunized (F1----C57BL/6) chimeras, when transferred into T cell-depleted B cell mice of F1 or C57BL/6 strain, produced comparable immune responses in both groups but induced much more severe arthritis in F1 than in C57BL/6 recipients. These results indicate that: i) two types of arthritis-resistant strains can be identified, each of which has anticollagen APC defect as a low responder and reduced T cell responsiveness as an intermediate responder and ii) a discrepancy between the degree of anticollagen responses and clinical arthritis is attributed to the differential susceptibility to anticollagen immune responses.     

H-2-linked Ir gene control of T cell recognition of the Sm nuclear autoantigen and the aberrant response of autoimmune MRL/Mp-+/+ mice

We have examined T cell recognition of the nuclear autoantigen Sm. Rabbit Sm-primed cells from autoimmune MRL/Mp-+/+ (+/+) mice and from all normal strains tested were able to proliferate to rabbit Sm in vitro. In contrast, the reactivity of normal strains to Sm of murine origin was genetically restricted; only H-2f strains B10.M and A.CA, and H-2s strains B10.S and A.SW could recognize mouse Sm, suggesting that responsiveness to mouse Sm was under the control of H-2-linked Ir genes. Although five Iak-bearing normal strains (B10.A, B10.A(2R), B10.BR, A/Sn, and CBA) did not recognize mouse Sm, autoimmune +/+ (Iak) mice were responders. The responsiveness of the +/+ mice to Sm was probably not due to differences in their Iak region, compared with other strains, because the Iak region of normal strains and the autoimmune +/+ strain were indistinguishable by interstrain MLC, immune response gene product function, and recognition by anti-Iak mAb. Inhibition of Sm-induced proliferation by mAb demonstrated that T cells from autoimmune +/+ mice, responder normal strains, and nonresponder normal strains recognized rabbit and mouse Sm in the context of I region-encoded products. The T cell response to Sm antigen in normal mice is therefore Ia region restricted and, for the murine antigen, under Ir gene control. Autoimmune mice that spontaneously make anti-Sm antibodies (+/+) also perceive Sm in an Ia-restricted manner, but their responder status abrogates H-2-linked Ir gene control.     

Genetic control of contact photosensitivity to tetrachlorosalicylanilide. II. Igh complex controls the sensitivity induced by photohapten-modified spleen cells but not epidermal cells

We studied the genetic control of murine contact photosensitivity (CPS)1 to 3,3',4',5-tetrachlorosalicylanilide (TCSA) that was induced by subcutaneous injection of TCSA-photomodified epidermal cells (photoTCSA-EC) and spleen cells (photoTCSA-SC). With regard to the H-2 locus, sensitization with both types of photohaptenated cells showed the same pattern of CPS responses: H-2k and H-2b,d haplotypes were closely associated with low and high responders, respectively. On the other hand, the Igh locus affected the CPS reaction induced by photoTCSA-SC but not -EC; the Igh-1d allotype was related to low responsiveness, while high responders possessed Igh-1a,b. Thus, the photoTCSA-SC sensitization was controlled by H-2 and Igh in a codominant manner. The photoTCSA-SC-induced responses of H-2k but not Igh-1d mice were enhanced by CY pretreatment, suggesting that the mechanisms of low responsiveness in H-2k and Igh-1d mice were different. H-2 identity between donors of photoTCSA-EC and recipients was sufficient for effective sensitization, whereas both H-2 and Igh between donors of photoTCSA-SC and recipients should be identical to obtain maximum sensitization. This further confirmed the involvement of the Igh complex in the genetic control of CPS evoked by photoTCSA-SC. B cells as well as macrophages served as an effective presentation template for the photoTCSA-SC sensitization in the high responder Igh-1a mice, whereas B cells failed in inducing the CPS reaction in the low responder Igh-1d mice. These results suggest that B cells play an essential role in the Igh control phenomenon seen in the photoTCSA-SC sensitization. The present study demonstrated that CPS induced by photohapten-modified cells are differentially regulated by the H-2 and Igh gene loci depending on the cell type used for sensitization.     

Non-H-2 linked control of low versus high responses of antigen-induced lymph node cell proliferation: possible role for antigen-presenting cells.

Quantitative differences in the magnitude of antigen-induced proliferative responses of sensitized lymph node cells between low (C3H/Anf or C3H/Cr) and high (C3H/Hej or CBA/j) responder H-2k mice have been observed 1 to 2 weeks after in vivo sensitization with antigen (OVA, PPD, and GAT). We have shown that antigen presentation is less effective in the sensitized lymph node cell populations from low responder mice compared with those from high responder mice, suggesting that the number and/or functional status of antigen-presenting cells in the regional lymph nodes may be a key factor in determining the magnitude of antigen-induced proliferative responses. These data are consistent with the hypothesis that cell traffic after sensitization plays an important role in determining the immune responsiveness of lymph nodes.     

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.     

Antigen-sensitized CD4+CD62Llow memory/effector T helper 2 cells can induce airway hyperresponsiveness in an antigen free setting

Background

Airway hyperresponsiveness (AHR) is one of the most prominent features of asthma, however, precise mechanisms for its induction have not been fully elucidated. We previously reported that systemic antigen sensitization alone directly induces AHR before development of eosinophilic airway inflammation in a mouse model of allergic airway inflammation, which suggests a critical role of antigen-specific systemic immune response itself in the induction of AHR. In the present study, we examined this possibility by cell transfer experiment, and then analyzed which cell source was essential for this process.

Methods

BALB/c mice were immunized with ovalbumin (OVA) twice. Spleen cells were obtained from the mice and were transferred in naive mice. Four days later, AHR was assessed. We carried out bronchoalveolar lavage (BAL) to analyze inflammation and cytokine production in the lung. Fluorescence and immunohistochemical studies were performed to identify T cells recruiting and proliferating in the lung or in the gut of the recipient. To determine the essential phenotype, spleen cells were column purified by antibody-coated microbeads with negative or positive selection, and transferred. Then, AHR was assessed.

Results

Transfer of spleen cells obtained from OVA-sensitized mice induced a moderate, but significant, AHR without airway antigen challenge in naive mice without airway eosinophilia. Immunization with T helper (Th) 1 elicited antigen (OVA with complete Freund''s adjuvant) did not induce the AHR. Transferred cells distributed among organs, and the cells proliferated in an antigen free setting for at least three days in the lung. This transfer-induced AHR persisted for one week. Interleukin-4 and 5 in the BAL fluid increased in the transferred mice. Immunoglobulin E was not involved in this transfer-induced AHR. Transfer of in vitro polarized CD4⁺ Th2 cells, but not Th1 cells, induced AHR. We finally clarified that CD4⁺CD62L^low memory/effector T cells recruited in the lung and proliferated, thus induced AHR.

Conclusion

These results suggest that antigen-sensitized memory/effector Th2 cells themselves play an important role for induction of basal AHR in an antigen free, eosinophil-independent setting. Therefore, regulation of CD4⁺ T cell-mediated immune response itself could be a critical therapeutic target for allergic asthma.     

Haplotype-specific suppression of T cell response to lactate dehydrogenase B in (responder x nonresponder)F1 mice

Mouse strains that express the Ek (Ek beta E-1k alpha) molecule are nonresponders (NR) to the enzyme lactate dehydrogenase B (LDHB) in terms of T cell proliferation. Nonresponsiveness is caused by T suppressor (Ts) cells recognizing LDHB in the context of Ek molecules on the antigen-presenting cells. The data presented here demonstrate that the Ek-restricted Ts cells function in (R x NR)F1 mice in a remarkable haplotype-specific fashion: they selectively interfere with the Ak (ANR)-restricted response, and do not affect the response channeled through the A molecules of the responder parent. This haplotype-specificity of suppression provides an explanation of the dominance of responsiveness in (R x NR)F1 mice.     

Transfer of the enhancing effect of respiratory syncytial virus infection on subsequent allergic airway sensitization by T lymphocytes.

In mice, respiratory syncytial virus (RSV) infection enhances allergic airway sensitization, resulting in lung eosinophilia and in airway hyperresponsiveness (AHR). The mechanisms by which RSV contributes to development of asthma and its effects on allergic airway sensitization in mice are not known. We tested whether these consequences of RSV infection can be adoptively transferred by T cells and whether depletion of T cell subsets prevents the effects of RSV infection on subsequent airway sensitization. Mononuclear cells, T lymphocytes, or CD4 or CD8 T cells from peribronchial lymph nodes (PBLN) of RSV-infected mice were transferred into naive BALB/c mice which were then exposed to OVA via the airways. Additionally, RSV-infected mice were depleted of CD4 or CD8 T cells following acute RSV infection but prior to airway sensitization. Following sensitization, airway responsiveness to inhaled methacholine, numbers of lung eosinophils, and levels of IFN-gamma, IL-4, and IL-5 in PBLN cell cultures were monitored. Transfer of T cells from RSV-infected mice resulted in increased eosinophil influx into the lungs, increased IL-5 production, and development of AHR following airway sensitization to allergen. Transfer of CD8 but not CD4 T cells from the PBLN of RSV-infected mice also resulted in AHR following 10 days of OVA exposure. Further, depletion of CD8 T cells prevented these consequences of RSV infection while CD4 T cell depletion reduced them. We conclude that T cells, in particular CD8 T cells, are critical in mediating RSV-induced development of lung eosinophilia and AHR following allergic airway sensitization.     

肾综合征出血热双价纯化疫苗（Vero细胞）病毒株的筛选及其免疫原性研究

选用在Vero细胞上初步适应的LR1（Ⅰ型）、R22（Ⅱ型）株病毒,经乳鼠脑或腹腔接种,收剖感染鼠脑并在Vero细胞传代适应,此收获病毒与直接以Vero细胞传代的病毒比较表明：抗原效价、毒力滴度有明显提高。用LR1、LR22株病毒感染的Vero细胞培养物制备单价粗制疫苗和双价精制纯化疫苗免疫家兔,经空斑减少中和试验检测中和抗体,结果表明经乳鼠和Vero细胞交替传代适应后的LR1、R22株病毒具有良好的抗原性和免疫原性。     

Is genetically related macrophage factor (GRF) a soluble immune response (Ir) gene product?

The possibility that the antigen-presenting "macrophages" interacting with helper cells either directly or via the intermediary action of a soluble factor consisting of Ia antigen and a fragment of immunogen, termed GRG (genetically related factor), are a site of Ir gene action was investigated by using the synthetic polypeptide antigen (T,G)-A--L. It was found that T cells from (responder x nonresponder) F1 mice were stimulated by responder "macrophages" or GRF derived from these cells but not by the nonresponder macrophages of GRF from these cells. This suggests that the defect in helper cell induction in nonresponders is at the level of the presenting cell and that the macrophage factor GRF is a soluble Ir gene product. This conclusion was supported by the observation that there was normal presenting cell and GRF function in nonresponders, mouse strains such as CBA that yield helper cells and helper factor with (T,G)-A--L and have defects elsehwere.     

Genetic restrictions of transfer of delayed-type hypersensitivity to sheep erythrocytes: local versus systemic transfer.

Regulation of the transfer of delayed-type hypersensitivity (DTH) reactions to SRBC was studied using two assays. In the systemic transfer, SRBC immune cells were transferred intravenously and the recipient challenged by injecting antigen into the footpad. In the local transfer assay, SRBC immune cells were mixed with antigen before transfer into the footpad of the recipient. These studies utilized B10.D2 and B10.BR mice which are congenic strains differing only at H-2 region. DTH reactions can be transferred across H-2 barriers using a local transfer assay. When the immune cells were transferred intravenously or depleted of adherent cells prior to local transfer, DTH reactions cannot be transferred to an H-2 congenic recipient. Spleen cells from naive mice syngeneic to the intravenously transferred cells supply the necessary accessory cell when mixed with the antigen prior to injection into the footpad. This accessory cell may be a macrophage.     

The autologous mixed lymphocyte reaction in strains of mice with autoimmune disease

We have studied the autologous mixed lymphocyte reaction (AMLR) in 3 strains of mice with autoimmune disease. T cell proliferation to autologous non-T cells occurs in young mice of these 3 strains (as it does in normal mice) but is absent or greatly reduced in older mice of strains with autoimmune disease. Reciprocal mixing experiments revealed that the defect in the AMLR of the older mice resides in the responder T cell population. Further analysis of the cells participating in the AMLR of young mice of the B/W F1 strain revealed that: 1) a Thy 1- and Ly1-positive responder cell was necessary at the start of the culture to initiate the AMLR; 2) the cells present after 5 days of culture contained very few, if any, Ly123 cells in the B/W F1 strain compared with the normal C57BL/6 strain; and 3) the stimulating cell appear to be a macrophage, and an Ia-bearing cell must be present for the reaction to occur.     

Genetic analysis of the relationship between interleukin production and worm rejection in Trichinella spiralis-infected inbred mice

The production of interleukin 1 (IL-1), IL-2, and IL-3 by peritoneal macrophages, mesenteric lymph node (MLN), or spleen cells from inbred strains of mice infected with Trichinella spiralis was examined. The mice belonged to the worm rejection phenotypes previously characterized as strong (NFS), intermediate (C3H, BUB, DBA/1, SWR, CBA, etc.), or weak (B10.Q, B10.BR, etc.). Strong responder NFS mice produced approximately twice as much IL-1 as intermediate responder C3Heb/Fe or weak responder B10.BR mice. IL-3 production varied slightly among strains but did not show any relationship to the phenotype of rejection (highest: C3Heb/Fe, B10.BR; lowest: B10.Q). Of 16 strains of inbred mice and 6 F1 hybrid crosses assessed, marked variations occurred in IL-2 production from MLN cells in response to T. spiralis antigen challenge in vitro. When 16 mouse strains were compared IL-2 production ranged from 5.1 units/ml (A/J) to 29.8 (NFS). Variations in IL-2 production among mouse strains did not relate directly to MHC haplotype, and the capacity of an individual strain to release IL-2 or IL-3 did not correlate with adult worm rejection phenotype. Genetic linkage studies proved that the gene(s) regulating IL-2 production in T. spiralis infection were not linked to the gene(s) regulating adult worm rejection. Regression analysis showed a weak correlation of high IL-2 production with weak worm rejection suggesting that IL-2 production or an associated process is a negative factor in primary worm rejection.     

Immune response to the p-azobenzenearsonate (ABA)-GAT conjugate: role of I region genes in the selective activation of ABA-specific or GAT-specific T helper cells

Immunization of GAT non-responders with ABA-GAT leads to the activation of ABA-specific T cells. These hapten specific T cells are Lyt-1+2- helper cells capable of inducing anti-ABA antibody responses in vivo or B cell activation in vitro. However, their activation does not modify the GAT non-responder phenotype. Immunization of GAT responder mice with ABA-GAT activates GAT-specific T cells, which can help anti-ABA and anti-GAT antibody responses. Since the responder and non-responder strains used in these experiments differ only in the alleles present in the I region, the results suggest that the selective activation of hapten- or carrier-specific T cells is controlled by I region genes. Yet sensitization of the two strains with ABA-KLH or ABA-Tyr induces KLH-specific or ABA-specific T cells, respectively. This provides further evidence that the use of an immunogenic carrier prevents the expression of the hapten-specific T cell clones present in the repertoire of both responder and non-responder animals. Macrophages from responder animals pulsed with ABA-GAT can present ABA and GAT determinants to T cells. Thus, the absence of ABA-specific T cells in responders primed with ABA-GAT and their presence in GAT non-responders reflects a competition between hapten- and carrier-specific T cells and not an epitope selection by macrophages. We discuss the significance of the results in terms of Ir genes determining the self-plus-antigen-specific T cell repertoire rather than controlling antigen presentation by macrophages.