Research Article: Interaction of CD99 and its ligand upregulates IL-6 and TNF-α upon T cell activation

Date Published: May 23, 2019

Publisher: Public Library of Science

Author(s): Nuchjira Takheaw, Papawadee Earwong, Witida Laopajon, Supansa Pata, Watchara Kasinrerk, Jean Kanellopoulos.


CD99 has been reported to be involved in T cell regulation. CD99 ligand involvement in the regulation of T cell activation has been postulated. In this study, recombinant CD99 proteins were produced and used as a tool for determining the role of CD99 and its ligand interaction. Recombinant CD99 proteins induced the upregulation of IL-6 and TNF-α expression, but not IFN-γ, in anti-CD3 monoclonal antibody activated T cells. The cytokine alteration was not observed in unstimulated T cells indicating the cytokine upregulation required the signal from T cell activation. The upregulation of IL-6 and TNF-α was, in addition, observed in CD3- mononuclear cell population including monocytes and NK cells. The recombinant CD99 proteins, however, did not affect either CD25, CD69 or MHC class II expression or T cell proliferation, upon T cell activation. The CD99 ligands were demonstrated to be expressed on monocytes, NK cells and dendritic cells, but not on B and T cells. Our results indicated the presence of CD99 ligands on leukocyte surface. Interaction between CD99 and its ligands involves the regulation of cytokine production.

Partial Text

Over the last several decades, ligands of several leukocyte surface molecules involving T cell regulation have been identified [1–3]. Uncovering these ligands is essential for understanding the precise immunoregulation mechanism [4]. In the accomplishment of this, the discovery of various leukocyte surface molecules and its ligands interaction will lead to the development of new approaches for treatment of various diseases, including inflammatory diseases and cancers. The PD-1/PD-L1 immune checkpoint blockage in cancer therapy [5–7], the interfering CD28 and CD80/CD86 binding with CTLA-4-Ig in the treatment of rheumatoid arthritis [8, 9] and using anti-CTLA-4 monoclonal antibody (mAb) for cancer treatment [5, 6, 10] are the best examples.

CD99 is a transmembrane glycoprotein expressed on various cell types [11, 12, 37]. Several functions of CD99 molecules have been reported, including the involvement in T cell activation [18–20, 38]. Co-ligation of CD3 and CD99 with agonistic antibodies induced translocation of T cell receptor (TCR), ζ and ε chains into lipid rafts and amplification of TCR signaling by which this mechanism differs from the activation of CD28 co-stimulatory molecule [29]. Stimulation with anti-CD99 and anti-CD3 mAbs without anti-CD28 mAb could induce T cell proliferation, CD25 upregulation and Th1 cytokine production [22, 39]. Controversially, the inhibition of T cell activation by anti-CD99 mAb has also been reported [28]. The functions of CD99 reported, however, were determined by employing specific mAb to mimic the binding of CD99 to its ligands expressed on cell surface. This made us imagine that CD99 ligands remain and play a role in immunoregulation.

In conclusion, we report here the presence of CD99 ligands on leukocyte surface. Interaction between CD99 and its ligand mediates the upregulation of pro-inflammatory cytokine expression. The interaction between CD99 and its ligands is probably involved in the inflammatory condition occurring in the body. Blockage of CD99 and its ligand may abolish the production of inflammatory cytokines and may be a new strategy for the treatment of inflammatory diseases.




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