CD2-CD58 Axis: Targets in Immune Synapse

The glycoprotein CD58 is a costimulatory receptor, and its natural ligand CD2 is mainly expressed on the surface of T/NK cells. The CD2-CD58 axis is essential for the formation of the immunological synapse, regulating immune cell activation and adhesion and triggering signaling in immune cells and target cells, respectively.1 Recent studies have highlighted the axis's relevance in cancer immunotherapy, suggesting its potential to enhance anti-tumor immunity and making it a promising target for therapeutic interventions. The CD2-CD58 axis is associated with the regulation of autoimmune diseases, immune evasion of tumors, antiviral responses, and immune rejection, and targeted therapies for this have been developed. For instance, Siplizumab is a promising monoclonal antibody targeting CD2, with implications for the treatment of type 1 diabetes and transplant rejection.2 Alefacept also targets CD2 and is already approved for psoriasis treatment. Sino Biological offers a wide range of recombinant CD2 and CD58 proteins and antibodies to support elucidating key interactions and pathways and shedding light on potential therapeutic strategies.

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Physiological and Pathological Roles

CD2, mainly found on T cells and NK cells, interacts with CD58 (LFA-3) on antigen-presenting cells like dendritic cells and macrophages (1). The CD2-CD58 axis is related to immune cell activation and adhesion (1). It is essential for the formation of the immunological synapse, which is key for immune responses. Pathologically, dysregulation of this axis is linked to autoimmune diseases, transplant rejection, and some cancers. Targeting this axis is promising in cancer immunotherapy, as it can enhance T cell responses against tumors and has implications in overcoming resistance to immune checkpoint blockade therapies. (1,3)

Bench to Bedside

The CD2-CD58 axis plays a crucial role in immune function and is a significant focus for developing new treatments for diseases, particularly cancers. In a recent study by Ho et al., it was revealed that this axis can be harnessed to activate CD28-CD8+ T-cells in cancer immunotherapy, amplifying anti-tumor immunity by disrupting CMTM6's regulation of the PD-L1 protein. This disruption renders cancer cells more susceptible to immune attacks, particularly in cases where resistance to traditional anti-PD-1 therapy is encountered.3 Efforts to target this axis are underway in clinical investigations (see Table 1). For instance, Siplizumab, a monoclonal antibody directed at CD2, is undergoing phase 2 trials for the treatment of type 1 diabetes and transplant rejection. Meanwhile, Alefacept, which targets a distinct pathway, has secured approval for psoriasis treatment, underscoring the promising potential of targeted immunotherapy.

Application in Research

Sino Biological’s products are frequently referenced in esteemed journals. Binder C. et al. employed recombinant human CD2 (Sino Biological) to explore the binding dynamics between Siplizumab and CD2 using an SPR assay (2). In another investigation, Miao et al. delved into the correlation between CMTM6 and CD58 expression in human cancers through IHC analysis employing validated anti-CD58 antibody (Cat#: 12409-R126, Sino Biological) (5). Additionally, Hamid et al. demonstrated a time-dependent increase in CD61 and CD103 at the points of contact between the T cell membrane and the bilayer, utilizing total internal reflection fluorescence microscopy with lipid bilayers coated with ICAM-1, E-cadherin, and CD58 proteins (Sino Biological) (6).

References

1. Zhang, Y., Liu, Q., Yang, S. & Liao, Q. CD58 Immunobiology at a Glance. Frontiers in Immunology vol. 12 Preprint at https://doi.org/10.3389/fimmu.2021.705260 (2021).
2. Binder, C. et al. Siplizumab Induces NK Cell Fratricide Through Antibody-Dependent Cell-Mediated Cytotoxicity. Front Immunol 12, (2021).
3. Ho, P. et al. The CD58-CD2 axis is co-regulated with PD-L1 via CMTM6 and shapes anti-tumor immunity. Cancer Cell 41, 1207-1221.e12 (2023).
4. Romain, G. et al. Multidimensional single-cell analysis identifies a role for CD2-CD58 interactions in clinical antitumor T cell responses. Journal of Clinical Investigation 132, (2022).
5. Miao, B. et al. CMTM6 shapes antitumor T cell response through modulating protein expression of CD58 and PD-L1. Cancer Cell 41, 1817-1828.e9 (2023).
6. Hamid, M. H. B. A. et al. Unconventional human CD61 pairing with CD103 promotes TCR signaling and antigen-specific T cell cytotoxicity. Nat Immunol (2024) doi:10.1038/s41590-024-01802-3.