Phenotypic and functional characterization of the CD6-ALCAM T-cell co-stimulatory pathway after allogeneic cell transplantation

Abstract

CD6 is a co-stimulatory receptor expressed on T cells that binds activated leukocyte cell adhesion molecule (ALCAM), expressed on antigen presenting cells, epithelial and endothelial tissues. The CD6-ALCAM pathway plays an integral role in modulating T-cell activation, proliferation, and trafficking. In this study we examined expression of CD6 by reconstituting T cells in 95 patients after allogeneic cell transplantation and evaluated the effects of itolizumab, an anti- CD6 monoclonal antibody, on T-cell activation. CD6 T cells reconstituted early after transplant with CD4 regulatory T cells (Treg)-expressing lower levels of CD6 compared to conventional CD4 T cells (Tcon) and CD8 T cells. After onset of acute graft-versus-host disease (aGvHD), CD6 expression was further reduced in Treg and CD8 T cells compared to healthy donors, while no difference was observed for Tcon. ALCAM expression was highest in plasmacytoid dendritic cells (pDC), lowest in myeloid dendritic cells (mDC) and intermediate in monocytes and was generally increased after aGvHD onset. Itolizumab inhibited CD4 and CD8 T-cell activation and proliferation in preGvHD samples, but inhibition was less prominent in samples collected after aGvHD onset, especially for CD8 T cells. Functional studies showed that itolizumab did not mediate direct cytolytic activity or antibody-dependent cytotoxicity in vitro. However, itolizumab efficiently abrogated the costimulatory activity of ALCAM on T-cell proliferation, activation and maturation. Our results identify the CD6-ALCAM pathway as a potential target for aGvHD control and a phase I/II study using itolizumab as first line treatment in combination with steroids for patients with aGvHD is currently ongoing (clinicaltrials gov. Identifier: NCT03763318).

Identification of CD8+ T cell - immune cell communications in ileal Crohn’s disease

“…Compared with control mice, CD6-deficient mice exhibited less severe disease in several murine autoimmune models, including experimental autoimmune encephalomyelitis, psoriasis, and uveitis ( 53 – 55 ). Consistent with these findings, a humanized anti-CD6 monoclonal antibody, itolizumab, has been shown to be effective for the treatment of psoriasis and rheumatoid arthritis ( 56 , 57 ), owing to its ability to inhibit T-cell activation, proliferation, and production of proinflammatory cytokines ( 58 , 59 ), and is being studied as a therapy for acute graft-vs-host disease ( 60 ). Intriguingly, CD6 is a risk susceptibility gene in IBD ( 61 ), and a higher proportion of CD4 + T cells derived from intestinal tissues from patients with IBD expressed CD6 compared with healthy subsets ( 62 ), indicating that CD6 could represent a potential therapeutic target in IBD.…”

Effects of circulating inflammatory proteins on spinal degenerative diseases: Evidence from genetic correlations and Mendelian randomization study

“…The glycoprotein known as CD6, which is mostly expressed on the surface of T cells, has received greater attention in the context of immunological disorders. 57 CD6 binding to activated leukocyte cell adhesion molecule (ALCAM) is the most classical signaling pathway, 58 and ALCAM+ perichondrial cells can participate in vascular invasion by recruiting osteoclasts, 59 so CD6 may be associated with osteoclast viability. CD6 transcripts generate multiple CD6 isoforms by alternative splicing.…”

Comparative glycoproteomics study on the surface of SKOV3 versus IOSE80 cell lines

“…The CD6 molecule (CD6_HUMAN, P30203) is a type 1 transmembrane glycoprotein expressed in the cell surface of T cells that binds to ALCAM to function as co-stimulatory molecules and take roles in modulating T-cell proliferation, activation, and trafficking ( Oh et al, 2019 ; Rambaldi et al, 2022 ). A recent study suggested that the anti-CD6 monoclonal antibody, UMCD6, enhanced killing of cancer cells through effects on NK and CD8 + cells ( Ruth et al, 2021 ).…”