Ir gene controlled carrier effects in the induction and elicitation of hapten-specific delayed-type hypersensitivity responses.

The genetic requirements of carrier recognition were examined in the priming and elicitation of hapten specific, T-cell mediated, delayed-type hypersensitivity (DTH) responses. It was shown that nitrophenyl acetyl-poly-(L-glu56-L-lys35-L-phe9) (NP-GLO) could prime for NP responses only in strains of mice which are Ir gene responders to GLO. In contrast to this requirement, NO-GLO could elicit an NP-specific response in NP-bovine gamma globulin primed mice, even in GLO nonresponder strains. Furthermore, the nonimmunogenic molecule, NP-GL, could elicit an NP-specific DTH response in animals primed with NP on an immunogenic carrier.

Hapten-specific T cell responses to 4-hydroxy-3-nitrophenyl acetyl. III. Interaction of effector suppressor T cells is restricted by H-2 and Igh-V genes.

4-Hydroxy-3-nitrophenyl acetyl (NP)-derivatized syngeneic spleen cells administered intravenously induced a population of suppressor T cells that could suppress mice previously primed to NP. The effect was demonstrable when the suppressor cells were transferred to NP-primed mice on the day of challenge for delayed-type hypersensitivity (DTH) responses. In contrast to the suppressor T cell population, which abrogates 5-iodo derivative of NP (NIP)-specific DTH responses when administered before antigen priming, the effector-phase suppressors did not efficiently suppress NIP-specific DTH responses, and were not lysed by treatment with antiidiotype plus complement. Adoptive transfer experiments between major histocompatibility complex and allotype congenic strains of mice allowed demonstration of both Igh-V and I-A restrictions in the transfer of this cell population. The implications of these data in terms of network theories and proposed cellular models for negative immunoregulation were discussed.

Hapten-specific T-cell responses to 4-hydroxy-3-nitrophenyl acetyl. I. Genetic control of delayed-type hypersensitivity by VH and I-A-region genes.

Hapten-specific delayed-type hypersensitivity (DTH) was induced in several strains of mice. (4-hydroxy-3-nitrophenyl)acetyl-bovine gamma globulin (NP-BGG)-primed mice which did not bear the Ig1b heavy-chain linkage group made a NP-specific DTH response when challenged with NP bovine serum albumin (BSA) and failed to respond to challenge with (4-hydroxy-5-iodo-3-nitrophenyl)acetyl-bovine serum albumin (NIP-BSA). Strains of NP-BGG-primed mice bearing the Ig1b allotype, including SJL, responded to challenges of either NP-BSA or NIP-BSA. F1 hybrids between a cross-reactive strain, C57BL/6, and two other noncross-reactive strains were cross-reactive. Genetic mapping of the NIP-cross-reactive DTH response localized the trait to the VH-region of the Ig1b heavy-chain linkage group. The fine-specificity pattern of the T-cell anti-NP response, and the genetic mapping of this trait, were analogous to the reported fine specificity and mapping data of the humoral heteroclitic anti-NP response. Adoptive transfer studies on the ability to transfer NP-specific DTH between various strain combinations showed that the T-cell donors and the recipient must have homology for at least the I-A subregion. Whenever NP-specific reactivity was transferred from a strain which cross-reactively responded to NIP, the recipient also responded to both NP and NIP. The implications of the control of NP-primed DTH-reactive populations of T cells by two distinct genetic regions, VH and H-2, were discussed.

Hapten-specific T cell responses to 4-hydroxy-3-nitrophenyl acetyl. V. Role of idiotypes in the suppressor pathway.

4-Hydroxy-3-nitrophenyl (NP) derivatized syngeneic spleen cells injected intravenously stimulate maturation of an antigen-binding, idiotype-bearing induction-phase suppressor cell population, as well as an idiotype-binding anti-idiotype-bearing effector-phase suppressor cell population. Both cell types are present simultaneously in the spleen cell population 7-d after their induction. Furthermore, the cell population with antigen-binding properties can, in the presence of NP-derivatized syngeneic cells, induce a population of effector suppressor cells. The precursors of the effector suppressor population are not sensitive to concentrations of cyclophosphamide which prevented the generation of induction phase suppressor cells. These data provide direct evidence in support of the theory of network regulation of immune suppression. X

Hapten-specific T cell responses to 4-hydroxy-3-nitrophenyl acetyl. VII. Idiotype-specific suppression of plaque-forming cell responses.

The ability of suppressor cells induced by the intravenous administration of 4-hydro-3-nitrophenyl acetyl (NP)-modified syngeneic cells to reduce an idiotypic B cell response was studied in both an in vivo and an in vitro system. Idiotype-positive B cells were assayed by the ability of guinea pig anti-idiotypic antiserum to specifically inhibit idiotype-positive plaque formation. It was found that up to 57% of the PFC response in vivo and 100% of the PFC response in vitro was inhibitable with antiidiotypic antiserum. The expression of these idiotype-positive B cells could be suppressed by the transfer of spleen cells form mice treated 7 d previously with NP coupled syngeneic cels. T cells are both required and sufficient for the transfer of idiotype specific suppression. The induction of these idiotype-specific T suppressor cells directly with antigen suggests that recognition of unique determinants on cell surfaces is important for regulation of lymphoid cell interactions. The role of idiotype-specific suppressor cells in the network of lymphoid interactions is discussed.

Hapten-specific T-cell responses to 4-hydroxy-3-nitrophenyl acetyl. II. Demonstration of idiotypic determinants on suppressor T cells.

The ability of NP-coupled syngeneic spleen cells to induce antigen-specific T-suppressor cells capable of binding to NP-BSA-coated Petri dishes and mediating transfer of specific suppressive activity to NP was demonstrated. Furthermore, in strains of mice bearing the Ig-1b allotype, including SJL, and in (non-Ig-1b x Ig-1b)F1 hybrids, the NP-specific suppressor cells also interferes with expression of immunity after priming with NIP-BGG. Anti-NPb anti-idiotype antiserum plus complement treatment effectively abrogated the ability to transfer suppression. Formal genetic mapping of the fine specificity of cross-reactivity with Ig-1 allotypic congenic mice implies that expression of this trait is linked to the Ig-1b heavy chain linkage group. The sensitivity of NP-suppressor cells of appropriate strains to anti-idiotype treatment was also consistent with the formal mapping data. These experiments suggest that there are shared V-region structures on antibody and T cells that are crucial in the suppression pathway for the same antigen.

Anti-receptor antibody-induced suppression of murine H-Y-specific delayed-type hypersensitivity responses.

A putative anti-H-Y receptor antiserum (ARA) was raised in C57BL/6 male mice against splenic T lymphocytes from syngeneic females immunized against H-Y antigen. When this antiserum is given i.v. to C57BL/6 females it prevents the expression of H-Y-specific delayed-type hypersensitivity (DTH). The suppressive activity in ARA was selectively retained on rabbit anti-mouse immunoglobulin columns, and could be absorbed by H-Y-immune spleen cells from C57BL/6 female mice. The abrogation of H-Y DTH reactivity was at least in part due to the generation of suppressor T cells which are generated by ARA in naive female mice. ARA-generated suppressor cells specifically inhibit the induction phase of DTH responses to the H-Y antigen, having no effect on (4-hydroxy-3-nitrophenyl)acetyl (NP)-specific cutaneous sensitivity responses or on DTH responses to minor histocompatibility antigens. Furthermore, there is a requirement for Igh gene homology between the strain producing the ARA and the strain in which the DTH response is induced. Thus, C57BL/6 ARA given to A.BY (H-2b, Igh-1e) or to B.C-8 (H-2b, Igh-1a) mice was unable to suppress homologous H-Y DTH responses in these strains. However, C57BL/6 ARA induced suppressor cells in B.C-8 mice which were capable of inhibiting H-Y DTH responses when adoptively transferred to C57BL/6 females.

Hapten-specific T cell responses to 4-hydroxy-3-nitrophenyl acetyl.

The primary anti-(4-hydroxy-3-nitrophenyl)acetyl (NP) antibody response is known to have a heteroclitic fine specificity, i.e., anti-NP antibodies bind (4-hydroxy-5-iodo-3-nitrophenyl)acetyl (NIP) with greater affinity than NP itself. Past studies of NP-specific DTH responses and NP-specific T cell-mediated suppression have demonstrated sharing of fine specificity patterns and idiotypic structure between receptors on NP-specific T cells and anti-NP antibodies. We now analyze the fine specificity of NP-specific cutaneous sensitivity (CS) reactions to NP-O-succinimide (NP-O-Su) and NIP-O-succinimide (NIP-O-Su). The specificity of these responses is shown to be controlled by genes in the Igh gene complex. Cross-reactive CS responses induced by NP-O-Su elicited by NIP-O-Su were observed in strains of mice possessing the Igh-1b allotype but not in strains bearing the Igh-1c or Igh-1j allotypes. The CS reactivity could be adoptively transferred to naive recipients, and the ability of transfer CS reactivity was T cell dependent. In contrast to the genetic requirement for I-A region homology to adoptively transfer DTH reactions, compatibility at either the H-2K, H-21, or H-2D regions was sufficient to transfer NP-specific CS reactivity to naive recipients. Furthermore, in contrast to DTH responses, cyclophosphamide pretreatment was not required to induce CS responsiveness. Thus, the specificity of NP-O-Su-induced CS responses is controlled by both H-2- and Igh-linked genes.