The involvement of suppressor T cells in Ir gene regulation of secondary antibody responses of primed (responder X nonresponder)F1 mice to macrophage-bound L-glutamic acid60-L-alanine30-L-tyrosine.

Abstract

(Responder [R] X nonresponder [NR])F1 mice give indistinguishable primary in vitro plaque-forming cell (PFC) responses to either R or NR parental macrophages (Mphi) pulsed with the Ir-gene controlled antigen L-glutamic acid60-L-alanine30-L-tyrosine10 (GAT). However, such (R X NR)F1 mice, if primed to GAT, retained in vitro responsiveness to GAT-R-Mphi, but no longer responded to GAT-NR-Mphi. This suggested (a) a possible Mphi-related locus for Ir gene activity in this model, and (b) the occurrence of active suppression after priming with GAT leading to a selective loss of the usual primary responsiveness of (R X NR)F1 mice to GAT-NR-Mphi. This latter interpretation was tested in the current study. [Responder C57BL/6 (H-2b) X nonresponder DBA/1 (H-2q)]F1 mice were primed with 100 microgram GAT in pertussis adjuvant. 4-8 wk later, spleen cells from such mice were tested alone or mixed with normal unprimed F1 spleen cells for PFC responses to GAT-R-Mphi and GAT-NR-Mphi. The primed cells failed to respond to GAT-NR-Mphi, and moreover, actively suppressed the normal response of unprimed F1 cells to GAT-NR-Mphi. If the primed spleen cell donor had been treated with 5 mg/kg cyclophosphamide 3 days before priming or with 5-10 microliter/day of an antiserum to the I-Jb subregion [B10.A(5R) anti B10.A(3R)] during the first 4 days postpriming (both procedures known to inhibit suppressor T-cell activity), cells from such mice responded in secondary culture to both GAT-R-Mphi and also GAT-NR-MPhi. In addition, such spleen cells no longer were capable of suppressing normal F1 cells in response to GAT-NR-Mphi. Similar data were obtained using [CBA (H-2k) X DBA/1 (H-2q)]F1. Further, it was shown that (a) primary responsiveness to GAT-NR-Mphi was not an artifact of in vitro Mphi pulsing, because in vivo GAT-pulsed Mphi showed the same activity and (b) the secondary restriction for Mphi-antigen presentation was controlled by H-2 linked genes. These data suggest an important role for suppressor T cells in H-2 restricted secondary PFC responses, and also provide additional support for the hypothesis that Ir-gene controlled differences in Mphi antigen presentation are related to both suppressor cell generation and overall responsiveness in the GAT model.

Epitope-Specific Regulation of the Antibody Response against Alpha-Lactalbumins in the Mouse

“…This possibility has been examined and dis cussed in several other reports [8,26,27], where re sponsiveness to Ir-gene-controlled antigens was dom inant. It is most likely that the BoALA-specific Ts in duced by LR type APC was able to suppress BoALAspecific Th recognizing the class II of H-2S but not of H-2k.…”

FEMALE POPLITEAL LYMPH NODE RESPONSES TO H‐Y ANTIGEN ON MALE THYMOCYTES IN MICE: I. REGULATION OF PRIMARY AND SECONDARY RESPONSES BY H‐2‐ASSOCIATED Ir GENES

“…Of interest is the high secondary PLN response to B10 male cells in (B10 x 4R)F, and (BlO x BlO.AKM)F, hybrids ( Table 5), since all the parental strains responded to H-Y antigen with a low secondary response. This observation is reminiscent of the gene complementation phenomenon described in a number of systems (for review see Benacerraf & Germain, 1978;Dorf, 1981), including the cytotoxic reactions of T lymphocytes to H-Y antigen (Hurme et al, 1977(Hurme et al, , 1978a. It therefore seems that genes not only to the right but also to the left of the E, locus are in some cases involved in the control of the secondary PLN response to H-Y antigen, since for example the (B10 x 4R)F, hybrids did not differ from strain B10 by the alleles present in the chromosomal segment between E , and D loci, and yet the secondary response was different (Table 5).…”

“…This assumption is based on observatian of the secondary response of the same strength in strains BIO.A and B10.D2, strain B1O.A sharing the above segment plus the H-2D region with strain B10.D2 (Table 4) Results from studies of the secondary in vitro anti-H-Y cytotoxic T cell response have also suggested that the immune response to H-Y antigen is genetically controlled by two different genes (or two groups of genes) (Hurme et al, 1977(Hurme et al, , 1978a. Indeed, there are many data in the literature which show that the immune response to different membrane antigens is controlled by two genes that most often map to the A and E-C or C-S chromosomal segments (Benacerraf & Germain, 1978;Berzofsky, 1978;Kolsch & Falkenberg, 1978;Okuda el al., 1979;Dorf, 1981;Milich et al, 1984). At present our results cannot be explained on the basis of recent data demonstrating that a particular 'Ir gene phenotype' results from the interaction of gene products of the four known genes A,,…”

“…Thus, the genetic control of PLN responses to H-Y antigen, particularly in F, hybrids, cannot be explained by a single mechanism, e.g. a defect in antigen presentation and recognition (Benacerraf, 1978), dominance of suppressor T cell responses (Germain & Benacerraf, 1978;Pierce & Kapp, 1978), or simple gene complementation, as has been described for some synthetic co-polymers . The genetic regulation of immune responses may be involved in various stages of the immune processes, from antigen processing and presentation through multiple co-operations of the cell populations to maturation and proliferation of the effector cells.…”

When All Is Said And Done..

“…Furthermore, this inability of GAT-primed (b x q) FI T cells to respond to GAT-pulsed H-2q macro phages was the result of specifi c suppression of that particular MHC-restricted response; this effect was not observed if the cells had been challenged with responder H-2b GAT-pulsed macrophages (76). In addition, we pretreated with small doses of cyclophosphamide previous to priming the Fl animals with GAT (a protocol that we have shown does away with the ability of the mice to generate suppressor T cells in the GAT and GT systems-77).…”