Regulatory mechanisms in cell-mediated immune responses. VIII. Differential expression of I-region determinants by suppressor cells and their targets in suppression of mixed leukocyte reactions.

Abstract

The phenotypic expression of I-region determinants on cells producing and responding to MLR suppressor factor (MLR-TsF) was established in these studies. Alloantigen-activated MLR suppressor T cells (MLR-Ts), which produce MLR-TsF bearing gene products of the I-C subregion, were exposed to anti-I subregion sera and complement (C) before in vitro culture for MLR-TsF production. Suppressor activity was prevented by removal of cells bearing I-C determinants, whereas elimination of cells expressing I-A/B determinants had no effect. Interestingly, cytotoxic elimination of cells displaying I-J determinants also prevented MLR-TsF production. Admixture of anti-I-J and I-C antiserum-treated cells for MLR-TsF production failed to reconstitute suppressor activity, indicating that I-C and I-J gene products are expressed on a single population of cells critical to MLR suppression, rather than on distinct interacting subpopulations. Anti-I-C serum activity specific for I-C+ MLR-Ts was removed by adsorption with nylon wool-nonadherent splenic T cells and concanavalin A-activated thymocytes; adsorption with splenic B cells from anti-Thy-1,2 serum and C-treated spleen failed to remove relevant anti-I-C activity. These data suggest that regulatory I-C molecules, like I-J molecules, are preferentially expressed on T lymphocytes. Expression of I-C, or other I-region molecules on responder cell targets of MLR-TsF activity was also investigated. Responder cells were pretreated with anti-I subregion-specific sera in blocking or complement-dependent cytotoxic protocols before addition to MLR with MLR-TsF. Neither blocking nor the cytotoxic removal of cells bearing I-C or other I-region determinants from MLR responder populations interfered with MLR-TsF suppression. Because it has previously been demonstrated that MLR-TsF interacts optimally with activated, I-C syngeneic target cells, blocking and cytotoxic studies with anti-I subregion sera were also performed with responder cells activated by 24 h culture in MLR in the absence of MLR-TsF. Brief MLR-TsF pulse after antiserum treatment generated marked suppression regardless of blocking or absence of cells bearing serologically detected I-region determinants. I-C restricted suppression may thus be mediated not by interaction with I-C-bearing cells, but by target cells which exist in requisite association with populations of I-C+ cells.

Specific Suppressor T‐Cells Immune to Antigens of the H‐2 Complex: Receptors, Clonal Structure, Genetic Restriction and Antigenic Markers

“…These results are in agreement with the data on the same marker expression on a non-specific anti-H-2 suppressor T-cell-TsF producer (Rich & David 1979). The I-C expression seems to be the property of any MHC-induced T-suppressors independent of their antigenic specificity.…”

“…The requirement for identity in either the I-C subregion atone or the I-A -|-I-J -I-I-E complex between SSTC and the responders in MLC is indicative of dual recognition: SSTC interact with antigenic determinant by the antigen-specific receptors and, besides, they contact T-responders identical lo themselves in the indicated I-subregions. Requirements for suppressor-inhibited T cell homology in the I-C subregion (Rich et al 1979) or in one of the subregions (I-C or I-A) (Chensue et al 1983) were demonstrated in the other experimental systems.…”

“…The first possibihty seems to be most probable because the SSTC interaction with the I-C subregioD-identical responder T-lymphocyte is eliminated (and suppression is not seen) after the shielding of the I-C-product on the SSTC surface by anti-I-C antibodies (see above). The possibility that such interaction could be mediated by a soluble I-C-bearing product, as was shown for the non-specific Tsuppressors (Rich et al 1979), is less probable for the SSTC, although it can not be rejected formally. In any case, the requirement for close location of the SSTC and their targets, the inhibited T-cells, has been demonstrated in various systems: St, stimulators; Sup, suppressors; R, responders, a: direct contact between suppressor and responder surfaces (arrow); b: contact through short distance mediator (m); c: prevention by SSTC of access to the stimulator.…”

Suppressor T cells activated in a primary in vitro response to non-major histocompatibility alloantigens.

“…If these I-J-suppressor cells do indeed mask a Tc response to non-H-2 alloantigens, the interpretation of our earlier finding that pretreatment of a responder spleen cell population with an anti-Ia serum, which included a high titer of anti-I-J activity, and C led to significant primary anti-minor locus response was probably incorrect (16). As I-J-encoded determinants have been demonstrated on suppressor cells in a variety of systems (53)(54)(55), we interpreted the result as indicating that anti-Ia and C treatment removed a suppressor cell and thus facilitated a non-H-2 alloantigen-specific Tc response. It is possible that the suppressor expresses some Ia determinant(s) other than I-J, because the antiserum which was prepared in the mouse combination (B 10.HTT X A.TH)F1 anti-A.TL also contained strong anti-I-A k specificities.…”

INACTIVATION OF SPECIFIC ANTI‐H‐2 SUPPRESSOR T CELLS BY ANTISERA TO I‐J AND I‐C SUBREGION PRODUCTS OF THE H‐2 COMPLEX

“…Nonetheless, the H-2 complex is thought to control the functions, not of SSTC directly, but rather of their humoral factors, whose suppressive activity requires homology either in the I-J subregion (Pierres et al, 1979;Taniguchi & Tokuhisa, 1980) or in the KID region of the H-2 complex (Moorhead, 1979) between the factor and the acceptor T cells responsive to it. Besides, requirement for such a homology in the Z-C subregion has been shown where T cell proliferation in the mixed lymphocyte reaction (MLR) is inhibited by a factor from non-specific suppressor T cells induced with H-2 antigens (Rich et al, 1979). The function of anti-virus non-specific SSTC may be restricted by the D region of the H-2 complex (Humar & Bennett, 1977).…”