Abstract
The glycoprotein CD2 is a costimulatory receptor expressed mainly on T and NK cells that binds to LFA3, a cell surface protein expressed on e.g., antigen-presenting cells. CD2 has an important role in the formation and organization of the immunological synapse that is formed between T cells and antigen-presenting cells upon cell-cell conjugation and associated intracellular signaling. CD2 expression is upregulated on memory T cells as well as activated T cells and plays an important role in activation of memory T cells despite the coexistence of several other costimulatory pathways. Anti-CD2 monoclonal antibodies have been shown to induce immune modulatory effects in vitro and clinical studies have proven the safety and efficacy of CD2-targeting biologics. Investigators have highlighted that the lack of attention to the CD2/LFA3 costimulatory pathway is a missed opportunity. Overall, CD2 is an attractive target for monoclonal antibodies intended for treatment of pathologies characterized by undesired T cell activation and offers an avenue to more selectively target memory T cells while favoring immune regulation.
Highlights
Costimulation is needed in addition to antigen-specific signaling through the T cell receptor CD3 complex (TCR/CD3) to achieve full T cell activation
Activated keratinocytes expressed LFA3 but did not express B7, while T cells found in psoriatic lesions expressed CD2 but not CD28 [118]. These findings indicate that CD2/LFA3 costimulation has an important role in the generation of T helper 1 (Th1) cells following T cell activation by non-professional Antigenpresenting cell (APC) in the epidermis
A phase I study of siplizumab added to chemotherapy for treatment of patients with peripheral T cell lymphoma resulted in 84.5% overall response rate (OR), with 62% of patients achieving complete remission (CR)
Summary
Costimulation is needed in addition to antigen-specific signaling through the T cell receptor CD3 complex (TCR/CD3) to achieve full T cell activation. CD2 influences rearrangement of the actin cytoskeleton and agonistic cell signaling These two functions seem to be spatially separated as a fraction of CD2 molecules transitions to lipid rafts in the cell membrane upon cell activation where it co-localizes with other signaling molecules important in transducing TCR/CD3- and costimulatory receptor-mediated signaling, e.g., activated protein tyrosine kinases [41, 54, 55]. While the mechanism is yet to be elucidated, CD2 may facilitate formation of the “pre-IS” during probing of APCs by T cells through its influence on T cell signaling or actin cytoskeleton rearrangement This may reduce the minimum required affinity of TCR/CD3 for pMHC to induce stable cell-cell conjugation and IS formation. Recent in vitro evidence has shown that CD2/LFA3 costimulation plays an important role in the differentiation of human T cells co-cultured with activated keratinocytes. Differences in the function of CD2 in T and NK cells would be especially important to consider for therapeutic applications
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