Rosetting T cells in Hodgkin lymphoma are activated by immunological synapse components HLA class II and CD58.

A unique feature of Hodgkin lymphoma (HL) is the presence of CD4+ T cells that surround, protect and promote survival of tumor cells. The adhesion molecules involved in this so-called T cell rosetting are important components of the immunological synapse (IS). However, it is unknown whether this synapse is fully assembled and leads to T cell activation by enabling interaction between the T cell receptor (TCR) and human leukocyte antigen class II (HLA-II). We established a novel rosetting model by co-culturing HLA-II matched PBMCs with HL cell lines and show IS formation with activation of rosetting T cells. HLA-II downregulation by CIITA-knockout did not affect the extent of rosetting, but almost completely abrogated T cell activation. Intriguingly, the level of CD58 expression correlated with the extent of rosette formation and CD58-knockout or CD2 blockade reduced both rosette formation and T cell activation. Extension of our findings to primary HL tissue by immunohistochemistry and proximity ligation assays showed interaction of CD2 with CD58 and TCR-associated CD4 with HLA-II. In conclusion, T cell rosetting in HL is established by formation of the IS and activation of rosetting T cells critically depends on both TCR-HLA-II and CD2-CD58 interaction.

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