The macrophage F4/80 receptor is required for the induction of antigen-specific efferent regulatory T cells in peripheral tolerance

Abstract

We show that the mouse macrophage-restricted F4/80 protein is not required for the development and distribution of tissue macrophages but is involved in the generation of antigen-specific efferent regulatory T (T reg) cells that suppress antigen-specific immunity. In the in vivo anterior chamber (a.c.)–associated immune deviation (ACAID) model of peripheral tolerance, a.c. inoculation of antigen into F4/80−/− mice was unable to induce efferent T reg cells and suppress delayed-type hypersensitivity (DTH) responses. Moreover, the use of anti-F4/80 mAb and F4/80−/− APCs in an in vitro ACAID model showed that all APC cells in the culture must be able to express F4/80 protein if efferent T reg cells were to be generated. In a low-dose oral tolerance model, WT but not F4/80−/− mice generated an efferent CD8+ T reg cell population that suppressed an antigen-specific DTH response. Peripheral tolerance was restored in F4/80−/− mice by adoptive transfer of F4/80+ APCs in both peripheral tolerance models, indicating a central role for the F4/80 molecule in the generation of efferent CD8+ T reg cells.

F4/80 and the related adhesion‐GPCRs

“…F4/80 KO animals show normal development of tissue Mf populations [7] and normal responses to infectious challenge with Listeria [18]. On the basis of previous studies with the ACAID (anterior chamber-associated immune deviation) model, Stein-Streilein and colleagues provided evidence that the F4/80 molecule is required for peripheral tolerance to ovalbumin administered in the anterior chamber of the eye, as well as for low-dose oral tolerance [7]. F4/80…”

“…Subsequent cloning by Andrew McKnight et al [5] revealed that F4/80 is a seven-span transmembrane molecule with a large extracellular domain consisting of multiple EGF modules, and is related to another myeloid antigen, CD97, described by Jörg Hamann et al [6]. No natural ligand has been defined for F4/80 and its function remained mysterious till studies on F4/80 knockout mice, by Hsi-Hsien Lin, Joan Stein-Streilein and colleagues, who revealed a role in peripheral tolerance [7].…”

Characterization and functional study of a cluster of four highly conserved orphan adhesion‐GPCR in mouse

“…The functional contexts in which different aGPCR paralogs serve is very diverse, ranging from immunity, synapse function, planar cell polarity, tumor progression, and fertility (Usui et al, 1999;Steinert et al, 2002;Davies et al, 2004;Lin et al, 2005). Unraveling aGPCR function has not been possible for most class members due to the lack of knowledge about physiological stimuli and intracellular coupling to signaling cascades, and suitable in vivo models.…”

EMR1, the human homolog of F4/80, is an eosinophil‐specific receptor

“…Although a cellular ligand might be anticipated, molecules interacting with F4/80 have not yet been identified. F4/80-deficient mice are healthy and do not show abnormalities in macrophage development and function [14,15]. However, Lin et al [15] have recently provided the first clue to the function of F4/80 by demonstrating a role in the induction of peripheral tolerance.…”