Antigen-specific suppressor factors of noncytotoxic CD8+ suppressor T cells downregulate antibody responses also to unrelated antigens when the latter are presented as covalently linked adducts with the specific antigen.

We had previously shown (i) that conjugates of a given antigen A (AgA) and monomethoxypolyethylene glycol (mPEG) induced AgA-specific tolerance in mice which was mediated by polyclonal CD8+ suppressor T (Ts) cells, as well as by soluble factor(s) of these cells (TsF), and (ii) that clones of nonhybridized CD8+ Ts cells could be derived from the above single cells, and monoclonal AgA-specific TsF could be released from these cloned cells. In the present study, we demonstrate that mice pretolerized by injection of AgA(mPEG)n are also unresponsive to an unrelated antigen B (AgB), or to its haptenated derivative AgB-Hpn, when AgB or AgB-Hpn is injected in the form of a covalent adduct with AgA, i.e., AgA-AgB or AgA-AgB-Hpn, but not when it is injected as a mixture with AgA; in this study human (myeloma) IgG (HIgG) served as AgA, and ovalbumin (OVA) or OVA-DNP3 served as AgB or AgB-Hpn. Moreover, this phenomenon was reproduced in vitro; i.e., Ts cells of mice tolerized with HIgG(mPEG)30, or the soluble monoclonal TsF of cloned Ts cells, exerted their associative suppressive effector function--in the obligatory presence of CD8+ T cells of syngeneic naive mice (Tn cells)--on antibody (Ab) formation to an Hp (DNP), when the Hp was present as a covalent adduct linked either directly to HIgG (e.g., HIgG-DNP7) or indirectly via OVA (as in HIgG-OVA-DNP3); however, no suppression of the anti-DNP Ab response was observed when OVA-DNP3 was present as a mixture with HIgG. Furthermore, it was established that the accessory cells involved in processing the specific Ag in the presence of the Ts cells were also downregulated, as reflected by their reduced capacity for presentation of the Ag to HIgG-specific helper T (Th) cells in proliferation assays. All these results demonstrate that (i) the phenomenon of linked immunological suppression may involve the downregulation of Th cells which recognize, concomitantly with the Ts cell, the appropriate epitopes of AgA and AgB on the same Ac cell, (ii) the downregulation of these Th cells may be a consequence of the downregulation of Ac cells by Ts cells interacting with the appropriate epitope(s) present on the Ac cells, and (iii) most remarkably the CD8+ Ts cells could be substituted by Tn cells "armed" with the specific monoclonal TsF.