Aggregated Immunoglobulin Protects Immune T Cells from Suppression: Dependence on Isotype, Fc Portion, and Macrophage FcγR

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.