GIF Inhibits Th Effector Generation by Acting on Antigen-Presenting B Cells

Abstract

Glycosylation-inhibiting factor (GIF) is a 13-kDa cytokine secreted from T cells. Administration of bioactive recombinant GIF inhibits IgG1 and IgE Ab responses in vivo. Treatment of B cells with the cytokine reduces the secretion of IgG1 and IgE induced by LPS and IL-4. To examine the effect on cognate T-B interaction, GIF was added to low-density B cells from MD4 transgenic (Tg) mice, which express B cell receptor specific for hen egg lysozyme (HEL). The B cells were subsequently pulsed with HEL-OVA conjugate and cultured with OVA-specific naive CD4 T cells from DO11.10 Tg mice. Treatment of Ag-presenting B cells with GIF reduced expansion and IL-2 secretion of naive T cells and rendered them hyporesponsive to antigenic restimulation, resulting in 50–95% reduction of IL-4 and IFN-γ secretion upon restimulation with Ag. GIF dramatically inhibited Th effector generation when it was added to B cells before pulsing with HEL-OVA, whereas it showed little to no effect when added after B cells were pulsed with Ag. GIF was more effective when B cells from MD4 Tg mice were pulsed with HEL-OVA than when they were pulsed with OVA. This cytokine did not affect Th effector generation when B cells or irradiated splenocytes pulsed with OVA323–339 peptide stimulated naive DO11.10 T cells. Confocal microscopy revealed that GIF inhibited internalization of HEL by B cells from MD4 Tg mice. Therefore, the cytokine may regulate early steps of Ag presentation involving B cell receptors to diminish Th effector generation from naive CD4 T cells.

Functional Polymorphisms in the Promoter Region of Macrophage Migration Inhibitory Factor and Atopy

“…MIF has recently been shown to be coded for by the same gene as glycosylationinhibiting factor (27); glycosylation-inhibiting factor has been described as an immunosuppressive cytokine in a series of studies of regulation of antigen-specific IgE responses (28). Glycosylationinhibiting factor is involved in antigen presentation involving B and T cell receptors and regulates generation of Th effectors from naive CD4 T cells (29), consequently regulating the balance of Th1/Th2-type immune responses. The importance of regulatory roles of MIF/glycosylation-inhibiting factor in antigenspecific immune responses is additional evidence that the MIF gene is a promising candidate for atopy or antigen-specific IgE responsiveness.…”

B Cells Capturing Antigen Conjugated with CpG Oligodeoxynucleotides Induce Th1 Cells by Elaborating IL-12

“…It has long been debated whether B cells can prime naive T cells (28 -32). Recent in vitro experiments using Ig transgenic (tg) mice demonstrated that B cells have the capacity of activating naive T cells for proliferation (33,34) and the development of Th2 cells (35) or unpolarized effector T cells (36). However, little is known about the ability of B cells to prime naive T cells for differentiation toward Th1 cells.…”

CD4 cell-secreted, posttranslationally modified cytokine GIF suppresses Th2 responses by inhibiting the initiation of IL-4 production

“…Mouse IL-2, IL-4, IL-5, IL-13, and IFN-␥ were measured by ELISA, as described before (28). TNF-␣ was measured using BD cytometric bead array (BD).…”