Human Dendritic Cells Express the Complement Receptor Immunoglobulin Which Regulates T Cell Responses

Abstract

The B7 family-related protein V-set and Ig containing 4 (VSIG4), also known as Z39Ig and Complement Immunoglobulin Receptor (CRIg), is the most recent of the complement receptors to be identified, with substantially distinct properties from the classical complement receptors. The receptor displays both phagocytosis-promoting and anti-inflammatory properties. The receptor has been reported to be exclusively expressed in macrophages. We now present evidence, that CRIg is also expressed in human monocyte-derived dendritic cells (MDDC), including on the cell surface, implicating its role in adaptive immunity. Three CRIg transcripts were detected and by Western blotting analysis both the known Long (L) and Short (S) forms were prominent but we also identified another form running between these two. Cytokines regulated the expression of CRIg on dendritic cells, leading to its up-or down regulation. Furthermore, the steroid dexamethasone markedly upregulated CRIg expression, and in co-culture experiments, the dexamethasone conditioned dendritic cells caused significant inhibition of the phytohemagglutinin-induced and alloantigen-induced T cell proliferation responses. In the alloantigen-induced response the production of IFNγ, TNF-α, IL-13, IL-4, and TGF-β1, were also significantly reduced in cultures with dexamethasone-treated DCs. Under these conditions dexamethasone conditioned DCs did not increase the percentage of regulatory T cells (Treg). Interestingly, this suppression could be overcome by the addition of an anti-CRIg monoclonal antibody to the cultures. Thus, CRIg expression may be a control point in dendritic cell function through which drugs and inflammatory mediators may exert their tolerogenic-or immunogenic-promoting effects on dendritic cells.

Complement Receptors and Their Role in Leukocyte Recruitment and Phagocytosis

“…In 2000, a novel human Z39Ig gene on chromosome X was reported, encoding a new member of the immunoglobulin superfamily (Langnaese et al, 2000 ). A few years later, the complement receptor of the immunoglobulin family (CRIg), also referred to as V-set and Ig domain (VSIG4)/B7 family-related protein or Z39Ig, was identified as a receptor expressed on tissue resident and sinusoidal macrophages, especially hepatic KCs, and more recently also on human monocyte derived dendritic cells ( Table 1 ) (Helmy et al, 2006 ; Munawara et al, 2019 ). CRIg is a type 1 transmembrane receptor with two alternatively spliced variants in humans: long huCRIg(L) and short huCRIg(S) ( Figure 2 ).…”

“…Interestingly, CRIg has also been found to be a negative regulator of T-lymphocyte responses in tissues. CRIg can function as a coinhibitory molecule of the B7/CD28 superfamily, suppressing T-lymphocyte proliferation and cytokine production, thereby maintaining peripheral T-lymphocyte tolerance in healthy tissues (Vogt et al, 2006 ; Yuan et al, 2017 ; Munawara et al, 2019 ). Interestingly, this inhibitory function is regulated by CRIg internalization when bound to C3b or iC3b (e.g., opsonized target), allowing an adequate T-lymphocyte response to progress during tissue inflammation (Fearon et al, 1981 ; Sengeløv et al, 1994 ).…”

Nasal systems immunology identifies inflammatory and tolerogenic myeloid cells that determine allergic outcome following challenge

“…Sub-cluster 1 contained cells expressing a monocyte-like profile FCN1, SELL, S100A8, S100A9, which corresponded to mo-DC or the recently described inflammatory DC3 population by Villani et al 18,34,35 . In contrast, sub-cluster 3 expressed higher levels of the regulatory/inhibitory genes FCER1A, FTL, FCGR2B, RGS2 7,36–39 and VSIG4 40,41 along with MAPkinase signaling pathway genes (FOS, FOSB, JUN, JUNB, DUSP1) (Figure 6E, Table S5) , which may represent the ‘non-inflammatory’ FCGR2B cDC2 described by Villani et al . 18 , but are also related to cellular stress response (Figure S7) .…”

Vitamin D upregulates the macrophage complement receptor immunoglobulin in innate immunity to microbial pathogens

“…In addition, CRIg is an important phagocytosis-promoting receptor able to mediate capture of bacterial, fungal, and parasitic pathogens 22 , with increased phagocytic rates compared with CR3 11 , 12 , 23 . We have previously used the Santa Cruz monoclonal antibody to block CRIg function in dendritic cell-mediated T-cell response 24 . Attempts to address this issue with this blocking approach led to difficulties in interpretation of results.…”