Frontline: Optimal T cell activation requires the engagement of CD6 and CD166

Abstract

The T cell surface glycoprotein, CD6 binds CD166 in the first example of an interaction between a scavenger receptor cysteine-rich domain and an immunoglobulin-like domain. We report that in human these proteins interact with a K D =0.4-1.0 ? M and K off n 0.4-0.63 s -1 , typical of many leukocyte membrane protein interactions. CD166 also interacts in a homophilic manner but with around 100-fold lower affinity (K D =29-48 ? M and K off n 5.3 s -1 ). At concentrations, that will block the CD6/CD166 interaction, soluble monomeric CD6 and CD166 inhibit antigen-specific human T cell responses. This is consistent with extracellular engagement between CD6 and CD166 being required for an optimal immune response.

The Lymphocyte Receptor CD6 Interacts with Syntenin-1, a Scaffolding Protein Containing PDZ Domains

“…In conclusion, we have identified syntenin-1 as the first intracellular partner reported for human CD6, a lymphocyte surface receptor involved in proper IS maturation (17) and T cell proliferation (17,18). The accumulation of syntenin-1 at the IS recalls that previously reported at the neural synapse and suggests that syntenin-1 (alone or in conjunction with other PDZ-containing proteins) may be relevant for processes that occur not only at the neural, but also the IS.…”

“…This represents not only the first reported protein-protein interaction involving the intracytoplasmic region of CD6, but also the first description of the involvement of syntenin-1 in the protein-protein interactions taking place during IS maturation. CD6 is a lymphocyte surface receptor, which mediates cell-to-cell interactions relevant to IS maturation (17) and T cell proliferative responses (17,18). However, the intracellular interactions responsible for these CD6-mediated effects are mostly unknown to date.…”

“…Moreover, CD6 accumulates at the central part of the mature immunological synapse (IS), where it colocalizes with TCR/CD3 and CD5 (17). More importantly, CD6 has been implicated in early T cell-APC contacts influencing IS maturation (17) and further T cell proliferative responses (17,18). In B cells, it has been reported that CD6 ligation protects from anti-IgM-mediated apoptosis through bcl-2 induction (19).…”

Immunological evaluation of rheumatoid arthritis patients treated with itolizumab

“…25,38,39 Itolizumab, an anti-CD6 mAb, has demonstrated clinical benefits, 33,40 as well as modulation of T cell proliferation and decrease of proinflammatory cytokine levels in psoriasis patients. 35 Studies have shown that itolizumab is not a T cell-depleting antibody when used as monotherapy both in Cuban RA 33 and psoriasis (unpublished data) patients.…”

“…22,23 The interaction between ALCAM and the CD6 molecule is one of the costimulatory pathways of T cell activation. 24,25 An anti-CD6 monoclonal antibody (mAb) that prevented renal and bone marrow graft rejection 26,27 was evaluated in multiple sclerosis patients, and a significant reduction in peripheral T cell counts was found. 28 More recently, the finding of CD6 as a susceptibility gene in multiple sclerosis, 29,30 as well as the overexpression of ALCAM and the presence of CD6+ T and B cells in salivary glands of patients with Sj€ ogren syndrome, 31 support the role of CD6 in pathological autoimmunity and reinforces its relevance for targeted therapy.…”