Induction of tolerance to human gamma-globulin in FcR gamma- and Fc gammaRII-deficient mice.
FcR gamma-deficient mice were used to examine the role of Fc gamma receptors in the induction of peripheral tolerance to human gamma-globulin (HGG). FcR gamma-deficient mice injected with HGG in adjuvant demonstrated a CD4+ T cell response to in vitro challenge with HGG, as assayed by proliferation, cytokine secretion, and Ag-specific help for B cell Ab production. In vitro kinetics of Ag-specific proliferation were similar in both conventional and knockout mice. Peripheral tolerance could be established in these mice with a single dose of deaggregated protein, despite the lack of functional Fc gammaRI, the high affinity receptor for monomeric IgG. Establishment of unresponsiveness was observed at both the T and B cell levels. T cell tolerance was manifested in the reduction of T cell helper function and Ag-induced release of Th1- and Th2-like cytokines, as well as decreased proliferation to Ag-specific stimulation. B cell tolerance was demonstrated in knockout and normal mice by failure to detect HGG-specific Ab production using an immunization protocol for Ab production that bypasses the need for Ag-specific T cells. These results demonstrate that induction of tolerance in CD4+ cells to HGG does not require transduction of a signal through Fc gammaRI. Furthermore, the ability to induce tolerance to HGG in B cells in Fc gammaRII-deficient mice suggests that down-regulation of Ag-specific B cells through Fc gammaRII is not the mechanism by which B cell tolerance is induced. However, Fc gammaRII plays a role in regulating the immune response since the Ab response to immunogenic HGG in Fc gammaRII-deficient mice is markedly enhanced.
Whitmer
K J
KJ
Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Romball
C G
CG
Weigle
W O
WO
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D006801:Humans; D007108:Immune Tolerance / Q000235:genetics*; D007111:Immunity, Cellular; D051379:Mice; D018345:Mice, Knockout; D011961:Receptors, Fc / Q000172:deficiency / Q000235:genetics* / Q000276:immunology; D005719:gamma-Globulins / Q000276:immunology*
D011961:Receptors, Fc; D005719:gamma-Globulins