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

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Abstract
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.