Figure 3.

Preferential localizations of T-cell subpopulations in cHL. CD4⁺ T-cells localize in close proximity of HRS cells and form the typical rosettes. In particular, PD-1⁺ T-cells and CTLA4⁺ T-cells have been identified in contact with HRS cells and promote local immune evasion; LAG3⁺ T-cells have been described in the vicinity of HRS cells by some, but not all, authors. They are supported by HRS-derived IL6, and secrete IL10 and TGF-β that promote HRS survival and further suppress local immunity. CD58/CD2 interaction is critical for the establishment of the immunological synapse between HRS and CD4⁺ T-cells, and sustains the IL2-mediated autocrine signaling that leads to reactive T-cell expansion. Functional polarization of these checkpoint-defined T-cell subpopulations has yet to be determined, albeit Th1 subset should be the most abundant. Most of rosetting CD4⁺ T-cells participate in inhibitory interactions with HRS cells and PD-L1⁺ macrophages, which are also enriched nearby HRS cells. Outside the neoplastic niche, here represented by the yellow area surrounding the HRS cell, there are Th17 cells, PD-L1^- macrophages, CD8⁺ lymphocytes (mostly EM Tc1, with some variations depending on EBV status, see text) and a few NK cells. These potentially hostile populations are usually kept far away from neoplastic cells.