CD318 is a ligand for CD6

Abstract

It has been proposed that CD6, an important regulator of T cells, functions by interacting with its currently identified ligand, CD166, but studies performed during the treatment of autoimmune conditions suggest that the CD6-CD166 interaction might not account for important functions of CD6 in autoimmune diseases. The antigen recognized by mAb 3A11 has been proposed as a new CD6 ligand distinct from CD166, yet the identity of it is hitherto unknown. We have identified this CD6 ligand as CD318, a cell surface protein previously found to be present on various epithelial cells and many tumor cells. We found that, like CD6 knockout (KO) mice, CD318 KO mice are also protected in experimental autoimmune encephalomyelitis. In humans, we found that CD318 is highly expressed in synovial tissues and participates in CD6-dependent adhesion of T cells to synovial fibroblasts. In addition, soluble CD318 is chemoattractive to T cells and levels of soluble CD318 are selectively and significantly elevated in the synovial fluid from patients with rheumatoid arthritis and juvenile inflammatory arthritis. These results establish CD318 as a ligand of CD6 and a potential target for the diagnosis and treatment of autoimmune diseases such as multiple sclerosis and inflammatory arthritis.C D6 is a marker of T cells and an important T-cell regulator (1). Recent genome-wide association studies also identified CD6 as a risk gene for multiple sclerosis (MS) (2-5), an autoimmune disease in which T cells play a vital role in the pathogenesis. CD6 is composed of three extracellular domains (domains 1, 2, and 3), and it functions by interacting with its ligand(s) (6). The domain 3 of CD6 has been shown to be the site that the identified CD6 ligand, CD166, also known as ALCAM (activated leukocyte cell adhesion molecule), binds to (7). However, anti-CD166 antibodies only partially blocked the binding of thymic epithelial cells to CD6-overexpressing COS cells, and mAbs blocking CD6-CD166 interactions do not abolish CD6 function (8, 9). Itolizumab, an anti-CD6 mAb developed in Cuba and approved in India for treating psoriasis, reduces pathogenic T-cell responses in patients with psoriasis, but this mAb binds to domain 1 of CD6 instead of domain 3, and it does not interfere with the CD6-CD166 interaction. Interestingly, UMCD6, a mouse antihuman CD6 mAb that we found highly effective in treating encephalomyelitis (EAE) in CD6 humanized mice, also fails to block the CD6-CD166 interaction. All these studies suggest the existence of an additional CD6 ligand, other than CD166, that binds to domain 1 of CD6, and could be critical for CD6 function in autoimmune conditions. Further studies using a CD6 fusion protein as a bait to pull down CD6-binding proteins from synovial fibroblast surface proteins showed the binding of three polypeptides (10). One of these polypeptides was identified as CD166, and the identities of the other two were unknown (11). A mAb termed 3A11 was developed, and the antigen recognized by this mAb was identified as the new ligand of ...

The role of CD6 in autoimmune diseases

“…15 This molecule was recently shown to be CD318, and CD318 has now been established as a second ligand of CD6 by multiple biochemical and molecular approaches. 16 CD318 is expressed by a variety of tissue cell types with which T cells interact in organ-targeted autoimmune diseases, but it is not expressed on cells of the immune system such as lymphocytes and myeloid cells. CD166 and CD318 bind to distinct domains of CD6, and it appears possible that CD6 could bind both ligands concurrently.…”

“…CD166 and CD318 bind to distinct domains of CD6, and it appears possible that CD6 could bind both ligands concurrently. 16 CD6 can also interact with innate immune stimuli, including both pathogen-associated (such as bacterial peptidoglycans) 17 and damage-associated (such as galectins) 18 stimuli. The functional significance of these binding properties in host defenses is not yet well understood.…”

“…When EAE was induced in these mice, its progression was halted by the administration of a mouse antihuman CD6 monoclonal antibody that recognizes domain 1 of CD6-the domain to which CD318 but not CD166 binds. 7 Moreover, CD318-/-mice were robustly protected from EAE 16 , but CD166-/-mice have been reported to have worse EAE than controls. 19 Thus, the role of CD6 in fomenting organ-targeted autoimmunity may specifically reflect CD6 interaction with CD318, which is expressed on key tissue cells in these diseases-neurons and endothelial cells in the brain, synovial fibroblasts in the joint and keratinocytes in the skin [13][14][15][16] .…”

“…For example, sCD318 is elevated in synovial fluid from patients with RA and juvenile inflammatory arthritis (JIA) and is chemotactic for T cells at concentrations similar to the levels in the synovial fluid of inflamed joints. 16 A novel ligand of CD166 (ILT3-immunoglobulin-like transcript 3) was recently described that, like CD6, is also expressed on T cells 23 ; whether these two T cell receptors for CD166 function cooperatively or antagonistically is yet to be determined. Importantly, the success of an anti-CD6 monoclonal antibody in the treatment of psoriasis seems likely to spur the testing of this and other CD6-targeting biologics in an expanding spectrum of human immune-mediated diseases.…”

Identification of CD318 (CDCP1) as novel prognostic marker in AML

“…CD318 (CUB domain containing protein-1, CDCP1) is a highly glycosylated single pass transmembrane protein expressed on mesenchymal and neural stem cells and fibroblasts and hematopoietic progenitors [4][5][6][7]. CD318 overexpression has been recently correlated with poor overall survival (OS) in colon, breast, Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00277-020-03907-9) contains supplementary material, which is available to authorized users.…”