Activating and inhibitory Fcγ receptors can differentially modulate T cell‐mediated autoimmunity

Abstract

The molecular bases responsible for the loss of T cell tolerance to myelin antigens leading to the onset of multiple sclerosis remain obscure. It has been shown that balanced signaling through activating and inhibitory receptors is critical for the maintenance of tolerance to self antigens in autoimmune disorders. However, although FccR have been shown to influence experimental autoimmune encephalomyelitis (EAE) development, their role during pathogenesis remains controversial. Here we have evaluated whether relative expression of activating (FccRIII) and inhibitory (FccRIIb) FccR can modulate myelin-specific T cell response, as well as the susceptibility to develop EAE in mice. While FccRIIb -/-mice showed a significant increase in EAE severity, an FccRIII deficiency protected mice from disease. In addition, FccRIIb -/-mice showed enhanced activation of myelin-specific effector T cells, which were significantly more effective at causing EAE in adoptive transfer experiments than were T cells from wild-type mice. In contrast, FccRIII -/-mice showed a significantly reduced activation of myelin-specific T cells and these cells failed to adoptively transfer EAE. Consistently, increased expansion of regulatory T cells (Treg) during EAE was observed only for FccRIII -/-mice, which were able to suppress disease when adoptively transferred to recipient mice. These findings suggest that the balance between activating and inhibitory FccR signaling can contribute to the maintenance of T cell tolerance to myelin antigens and modulate EAE progression.

FcγRIIB Inhibits the Development of Atherosclerosis in Low-Density Lipoprotein Receptor-Deficient Mice

“…Bolland and Ravetch (23) have previously reported an increase in CD4 + cells relative to CD8 + cells in the spleen and an elevated expression of the activation marker CD69 on splenic CD4 cells in FcgRIIBdeficient mice on a C57BL/6 background. Another study reported lower expression of FoxP3 on CD4 + cells in the inguinal lymph nodes in FcgRIIB-deficient mice compared with the control C57BL/6 mice and a higher incidence of experimental autoimmune encephalomyelitis (50). The findings in the current study are in accordance with the results presented in the two latter studies.…”

Important Role for FcγRIIB on B Lymphocytes for Mucosal Antigen-Induced Tolerance and Foxp3+ Regulatory T Cells

“…Based on this, the complete lack of oral tolerance after adoptive transfer of FcgRIIB addition, we found that adoptive transfer of FcgRIIB-expressing WT DCs to FcgRIIB 2/2 mice could restore the in vivo tolerogenic effect of Ag/CTB treatment in these mice, although apparently to a lesser extent than seen after transfer of FcgRIIB-expressing B cells; also different from the B cells, the transferred DCs failed to induce Ag-specific Foxp3 + Tregs in vivo. Normally, like other FcgRs, FcgRIIB is activated only after being cross-linked by IgG-Ag immune complexes (26,36). However, our results suggest that FcgRIIB on B cells may be activated by exposure to Ag/CTB, even in the absence of any IgG Ab, although the FcgRIIB-expressing B cells became even more effective in inducing tolerance and Tregs following treatment with IgG Ab immune-complexed Ag/CTB compared with Ag/CTB alone.…”

Recombinant Soluble Human FcγR1A (CD64A) Reduces Inflammation in Murine Collagen-Induced Arthritis

“…Humoral immune responses to immunization with type II collagen are dependent on APC activity, with Fc␥Rs playing key roles in dendritic cell maturation (32,33) and in the uptake and processing of ICs for MHC class I-and II-dependent Ag presentation (33)(34)(35)(36)(37)(38). Dendritic cells are found within the joints of arthritic humans and mice (39) and also appear capable of recycling ICs through Fc␥RIIB for presentation of intact Ag to B cells (40).…”