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

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.

Analysis of the Effects of the Bruton's tyrosine kinase (Btk) Inhibitor Ibrutinib on Monocyte Fcγ Receptor (FcγR) Function

“…Preparation of Heat-aggregated IgG-Human or mouse heataggregated IgG was prepared according to methods described previously (23). In brief, whole human or mouse IgG at a concentration of 350 g/ml in incomplete RPMI medium was incubated at 62°C in a water bath for 30 min and immediately placed on ice.…”

Induced Expression of FcγRIIIa (CD16a) on CD4+ T Cells Triggers Generation of IFN-γhigh Subset

“…Preparation of Aggregated Human ␥-Globulin, ICs, and Labels-Aggregated human ␥-globulin (AHG) was prepared as previously described (25). Purified ␥-globulin at 10 mg/ml in PBS was aggregated by heating at 63°C for 30 min.…”

Epicutaneous Immunization with Protein Antigen in the Presence of TLR4 Ligand Induces TCRαβ+CD4+ T Contrasuppressor Cells That Reverse Skin-Induced Suppression of Th1-Mediated Contact Sensitivity

“…One is nonspecific and is present in both immune and nonimmune animals (30). The second Tcs cell is Ag specific, shields immune cells against Ag-specific CD8 ϩ Ts cells, and is triggered by Ag-Ab complexes (31,32). Our present experiments add to this regulatory cell armamentarium a third type of Tcs.…”