Enhanced efferocytosis by dendritic cells underlies memory T-cell expansion and susceptibility to autoimmune disease in CD300f-deficient mice

Abstract

Homeostasis requires the immunologically silent clearance of apoptotic cells before they become pro-inflammatory necrotic cells. CD300f (CLM-1) is a phosphatidylserine receptor known to positively regulate efferocytosis by macrophages, and CD300f genedeficient mice are predisposed to develop a lupus-like disease. Here we show that, in contrast to CD300f function in macrophages, its expression inhibits efferocytosis by DC, and its deficiency leads to enhanced antigen processing and T-cell priming by these DC. The consequences are the expansion of memory T cells and increased ANA levels in aged CD300f-deficient mice, which predispose CD300f-deficient mice to develop an overt autoimmune disease when exposed to an overload of apoptotic cells, or an exacerbated autoimmunity when combined with FcγRIIB deficiency. Thus, our data demonstrates that CD300f helps to maintain immune homeostasis by promoting macrophage clearance of self-antigens, while conversely inhibiting DC uptake and presentation of self-antigens.

Dendritic cells expressing immunoreceptor CD300f are critical for controlling chronic gut inflammation

“…The inhibitory signals, initiated by SHP-1 phosphatase recruitment to CD300f, serve to stop efferocytosis, and correlate with SHP-1 expression levels (17). Our data indicate that CD300f might function differently depending on the available signaling capacity within a specific cell type (17,18). In macrophages, expression of CD300f generates positive signals that dominate over negative signals (17); however, in DCs the inhibitory cues dominate, as CD300f-expressing DCs show decreased efferocytosis compared with CD300f-deficient DCs.…”

“…After performing their antimicrobial functions, neutrophils undergo apoptosis, and are subsequently removed by phagocytes, mainly macrophages (32,33), promoting resolution of acute inflammation and a return to homeostasis (25). We have reported that the recognition of PS on ACs by CD300f mediates efferocytosis by phagocytes (16)(17)(18). Given this, we hypothesized that regulation of efferocytosis through CD300f might be involved in controlling inflammation in the gut.…”

“…For instance, Moshkovits et al did not detect CD300f expression on colonic macrophages or mast cells, and they failed to examine CD300f expression on DCs (34), whereas we detect CD300f expression on macrophages, DCs, neutrophils, and mast cells in colonic lamina propria (Supplemental Figure 11); similarly, Matsukawa et al (20) readily detected CD300f on the surface of colonic mast cells, macrophages, and eosinophils. The lack of detection of CD300f on lamina propria macrophages by Moshkovits and colleagues is surprising, as, in general, macrophages could be considered a hallmark of CD300f expression (18,(35)(36)(37). CD300f expression has been shown to be regulated by various cytokines (38,39), which could depend on exposure to environmental factors and/ or different microbiota communities present in the animal facilities.…”

“…Consequently, mouse CD300f has been shown to serve as either an activating or an inhibitory receptor (17,18,(45)(46)(47)(48). Our previous work showed that the CD300f cytoplasmic tail initiates either positive or negative signals for phagocytosis of ACs upon recognition of PS (17).…”

“…CD300f (also known as CLM-1), expressed mainly by myeloid cells, is a PS-recognizing receptor with a single IgV-like extracellular domain and an intracellular tail containing both tyrosine-based activating and inhibitory motifs, which regulates efferocytosis by professional phagocytes (16)(17)(18). Recently we have demonstrated that, in contrast to CD300f function on macrophages, its expression inhibits efferocytosis by DCs (18). However, how CD300f-mediated efferocytosis, especially by DCs, regulates acute and/or chronic inflammatory responses in vivo has not been determined.…”