We determined the regulatory properties of heat‐aggregated immunoglobulins (HA‐Ig) that possess many activities of immune complexes (IC), such as binding and activation of cells via immunoglobulin Fc γ receptors (FcγR). HA‐Ig protected contact sensitivity (CS) effector T cells from antigen‐specific immunosuppression, while monomeric IgG were inactive. This anti‐suppressive activity of HA‐Ig was antigen non‐specific, and depended on the species from which Ig was derived, i.e. mouse and rat HA‐Ig were protective in mice, and of other species were inactive. The protecting activity of HA‐Ig was confined to IgG2a and IgG3, and to a lesser degree to IgG1 isotypes, and resided in the Fc domain. Removal of phagocytic cells from the CS‐immune target cells, or blocking with anti‐FcγR mAb, abolished HA‐Ig protection of CS‐effector T cells from suppression. We suggest that HA‐Ig multimers acted via Fc domains, in one of two ways: by binding to FcγR of macrophages to produce positive‐acting cytokines, or by blocking FcγR on macrophages, to compete with suppressive factors that can also bind to FcγR. If HA‐Ig protection of T cells is generalized, it is likely that IC in vivo may non‐specifically overcome suppression of responses to antigen that normally are under the control of T suppressive cells, and thus may contribute to the development of autoimmunity.

The role of gamma delta T cells in immunoregulation is largely unknown. In the current study we noted that gamma delta T cells play a positive role in the humoral response. These positively acting gamma delta T cells are required for the successful adoptive cell transfer of the humoral response, as well as for in vitro generation of plaque-forming cells (PFC). The presented results show that gammadelta T cells cause an increase in interleukin-10 (IL-10) production, which partly elucidates the mechanism of action of these cells. However, experiments with cell culture inserts strongly suggest that direct cell-cell contact between immune and gamma delta H-2-compatible regulatory T cells is critical to the exertion of the positive immunoregulatory function of gamma delta cells. The mechanism of cross-talk between these two cell populations is still not clear but we regard as most likely that the positively acting gamma delta T cells may interact with a complex of heat-shock protein-non-polymorphic MHC (IB) on the surface of T helper type 2 and/or B cells. This could provide, by direct cell-cell contact, the cognate recognition between gamma delta T-cell receptors and heat-shock protein-MHC that leads to positive internal signalling in the immune cells.

Antigen-antibody complexes (IC) can up or down regulate immune responses by induction of immunoregulatory cells. We have studied the effect of mouse heat-aggregated immunoglobulin (Ig) (HA) which have many biological activities similar to IC on immunogenicity of TNP-substituted macrophages (TNP-Mphi). Our results show that: (1) mouse oil-induced peritoneal macrophages treated with HA produce in vitro significantly higher levels of interleukin (IL-1beta), tumor necrosis factor (TNF)-alpha, IL-6, IL-10 and particularly IL-12 and express more B7-1 and B7-2 and ICAM-1 cell surface costimulatory molecules than Mphi treated with monomeric Ig (MM); (2) Mphi derivatized with TNP, treated or not with MM, induce in vivo antigen-specific unresponsiveness. In contrast TNP-Mphi treated with HA induce significant contact sensitivity reaction even when injected into previously tolerized recipient animals. Treatment of recipients with anti-IL-12 Ab prevents immunization by TNP-Mphi-HA. These results indicate that bypass of tolerance by treatment of TNP-Mphi with HA is a result of an increased production of IL-12 by these cells and an enhanced expression of costimulatory molecules important in T cell-Mphi interactions. We suggest that a similar overcoming of tolerance through the action of IC may be responsible for the generation of autoantibodies of heterologous specificity in pathological conditions in which such complexes are formed.

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