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

Abstract

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.

CD58 Immunobiology at a Glance

“…The formation of T cell rosettes in HL relied on the IS, and activation of rosetting T lymphocytes is dependent on the CD2-CD58 interaction ( 201 ). Although CD58 mutations in primary Reed/Sternberg (HRS) cells are rare, inactivating mutations in CD58 are common in HL cell lines and relapsed HL patients ( 202 , 203 ).…”

The Evolving Knowledge on T and NK Cells in Classic Hodgkin Lymphoma: Insights into Novel Subsets Populating the Immune Microenvironment

“…Eliminating rosetting T-cells by targeting the HRS/T immunological synapse might be an additional manner to deprive the neoplastic niche of immunosuppressive populations. Because the CD2/CD58 interaction stabilizes the HRS/T synapses [ 75 ], monoclonal anti-CD2 antibodies, already in clinical trials for T-cell lymphomas and autoimmune conditions [ 102 ], may counter rosette formation and prove of some benefit in cHL. Lastly, recruitment of tumor-nurturing immune subsets can be blocked by acting on chemokine/chemokine receptor pairs.…”

“…The first one is critical to stabilize CD4 + T-lymphocytes in the close proximity of HRS cells. It is represented by CD58/CD2 and, to a lesser extent, MHC-II/TCR interactions, which form an immunological synapse between neoplastic and T cells, and lead to the local accumulation of rosetting T-cells [ 75 ]. The second type of interactions serves to dampen T-cell antitumor activity and includes PD1/PD-L1, CTLA4/CD86 and LAG3/MHC-II interactions [ 76 , 77 , 78 ].…”

Lymphocyte predominant Hodgkin lymphoma, antigen‐driven after all?

“…A potentially pathogenic relevant relation was found between IgD-positive NLPHL and infection with Moraxella catarrhalis, a common bacterium in the upper respiratory tract, based on the following findings [87]. [89]. An immunological synapse between HLA class II on the LP cells and the T-cell receptor on the rosetting T cells was demonstrated in IgD + as well as IgD − cases [90].…”

“…The MHC‐II haplotype predominance, together with the antigen‐specific RpoC stimulation, suggests a T‐cell component to this immune response. Immunological synapses between rosetting T‐cells and R‐S cells have been shown, involving interactions between CD58 and CD2 and HLA class II and CD4 [89]. An immunological synapse between HLA class II on the LP cells and the T‐cell receptor on the rosetting T cells was demonstrated in IgD + as well as IgD − cases [90].…”