Clinical and experimental evidence for targeting CD6 in immune-based disorders

Consuerga-Fernandez et al., 2018. Autoimmune Rev.

BACKGROUND: CD6 is a cell surface glycoprotein expressed by most T cells and a subset of B cells that has incompletely-defined roles in regulation of lymphocyte development, selection, activation and differentiation. The two main known mammalian CD6 ligands, CD166/ALCAM and the very recently reported CD318, are widely expressed by both immune cells and a wide range of other cell types, including various epithelial and mesenchymal cell types, as well as many neoplasms. Moreover, CD6 is also a receptor for several pathogen- and damage-associated molecular patterns. Further layers of complexity of CD6 function are implied by the existence of multiple CD6 isoforms generated by alternative splicing of CD6 transcripts and soluble forms of CD6 released by proteases from the lymphocyte surface. Multiple lines of evidence are now emerging to implicate CD6 and its ligands in the pathogenesis and potentially the treatment of human autoimmune diseases, such as multiple sclerosis and psoriasis. CD6 is an important multiple sclerosis risk gene, and mice genetically deficient in CD6 or CD318, or treated with antibodies or chimerical proteins that interfere with CD6-ligand interactions, are protected from experimental allergic encephalomyelitis, a mouse model of multiple sclerosis. CD6 deficient mice also show reduced TH17 differentiation and protection from disease in a moue model of psoriasis, providing a foundation for successful clinical trials of an anti-CD6 monoclonal antibody (Itolizumab) in psoriasis. Here we review current knowledge about CD6 and its ligands, and consider its potential value as a therapeutic target in a range of immune-mediated disorders.

Activated leucocyte cell adhesion molecule (ALCAM/CD166) regulates T cell responses in a murine model of food allergy

Kim et al., 2018 192: 151-164.

BACKGROUND: Food allergy is a major public health problem. Studies have shown that long-term interactions between activated leucocyte cell adhesion molecule (ALCAM/CD166) on the surface of antigen-presenting cells, and CD6, a costimulatory molecule, influence immune responses. However, there are currently no studies on the functions of ALCAM in food allergy. Therefore, we aimed to identify the functions of ALCAM in ovalbumin (OVA)-induced food allergy using ALCAM-deficient mice. Wild-type (WT) and ALCAM deficient (ALCAM–/–) mice were sensitized intraperitoneally and with orally fed OVA. The mice were killed, and parameters related to food allergy and T helper type 2 (Th2) immune responses were analysed. ALCAM serum levels increased and mRNA expression decreased in OVA-challenged WT mice. Serum immunoglobulin (Ig)E levels, Th2 cytokine mRNA and histological injuries were higher in OVA-challenged WT mice than in control mice, and these were attenuated in ALCAM–/– mice. T cell proliferation of total cells, CD31CD41 T cells and activated T cells in immune tissues were diminished in OVA-challenged ALCAM–/– mice. Proliferation of co-cultured T cells and dendritic cells (DCs) was decreased by the anti-CD6 antibody. In addition, WT mice sensitized by adoptive transfer of OVA-pulsed ALCAM–/– BM derived DCs showed reduced immune responses. Lastly, serum ALCAM levels were higher in children with food allergy than in control subjects. In this study, serum levels of ALCAM were elevated in food allergy-induced WT mice and children with food allergy. Moreover, immune responses and T cell activation were attenuated in OVA-challenged ALCAM–/– mice. These results indicate that ALCAM regulates food allergy by affecting T cell activation.

Failure of a T cell regulator: CD6 contributes to the aggravation of autoimmune inflammation

Meyer & Kofler, 2018. Cellular and Molecular Immunology.

BACKGROUND: The scavenger-like lymphocyte receptor CD6 is a regulator of T cell functions, and is associated with autoimmune diseases. However, the specific contribution of CD6 to autoimmunity remains unknown. Under physiological conditions, CD6 associates with the T cell antigen receptor (TCR)/CD3 complex at the center of the immunological synapse and regulates T cell responses through activation-dependent recruitment of the positive regulator SLP-76 and other downstream signaling effectors.1,2 In recent years, immune-activating and immune-inhibiting functions of CD6 have been reported, indicating a dual role of CD6 in T cell activation.1 It has been postulated that the strength of TCR activation determines whether CD6 enhances or inhibits TCR signaling. This possible counter-regulatory role of CD6 may contribute to the control of T cell responses.

The role of CD6 in autoimmune diseases

Fox, 2018.  Cellular & Molecular Immunology.

BACKGROUND: In a recent publication in the Cellular and Molecular Immunology, Consuega-Fernandez and colleagues present new data from patients with psoriasis, linking the CD6 lymphocyte surface structure to the pathogenesis of this disease. In this commentary, I will discuss these new findings in the context of accumulating evidence for important roles of CD6 in a variety of autoimmune disorders. Although CD6 was one of the earliest “CD antigens” to be described, it is only recently that attention has refocused on the potential for CD6 as a treatment target in immune-mediated diseases.

T cell activation and differentiation is modulated by a CD6 domain 1 antibody Itolizumab

Bughani et al., 2018. PLoS One. 12(7): e0180088

BACKGROUND: CD6 is associated with T-cell modulation and is implicated in several autoimmune diseases. We previously demonstrated that Itolizumab, a CD6 domain 1 (CD6D1) specific humanized monoclonal antibody, inhibited the proliferation and cytokine production by T lymphocytes stimulated with anti-CD3 antibody or when co-stimulated with ALCAM. Aberrant IL-17 producing CD4+ helper T-cells (Th17) have been identified as pivotal for the pathogenesis of certain inflammatory autoimmune disorders, including psoriasis. Itolizumab has demonstrated efficacy in human diseases known to have an IL-17 driven pathogenesis. Here, in in vitro experiments we show that by day 3 of human PBMC activation using anti-CD3 and anti-CD28 co-stimulation in a Th17 polarizing milieu, 15-35% of CD4+ T-cells overexpress CD6 and there is an establishment of differentiated Th17 cells. Addition of Itolizumab reduces the activation and differentiation of T cells to Th17 cells and decreases production of IL-17. These effects are associated with the reduction of key transcription factors pSTAT3 and RORgammaT. Further, transcription analysis studies in these conditions indicate that Itolizumab suppressed T cell activation by primarily reducing cell cycle, DNA transcription and translation associated genes. To understand the mechanism of this inhibition, we evaluated the effect of this anti-human CD6D1 mAb on ALCAM-CD6 as well as TCR-mediated T cell activation. We show that Itolizumab but not its F(ab’)2 fragment directly inhibits CD6 receptor hyper-phosphorylation and leads to subsequent decrease in associated ZAP70 kinase and docking protein SLP76. Since Itolizumab binds to CD6 expressed only on human and chimpanzee, we developed an antibody binding specifically to mouse CD6D1. This antibody successfully ameliorated the incidence of experimental autoimmune encephalitis in the mice model. These results position CD6 as a key molecule in sustaining the activation and differentiation of T cells and an important target for modulating autoimmune diseases.