Figure 5.

Immune synapse in a CLL node. This figure focuses on the germinal centers of lymph nodes. By combining data from several studies in lymph nodes and peripheral blood, we observe that PD-1 and PD-L1 are heterogeneously expressed markers of B lymphocytes from chronic lymphoid leukemia. Similarly, PD-1 is overexpressed in TLs infiltrating the CLL microenvironment. Within the malignant lymph node proliferation centers, PD-1+ CD4+ TLs are in close contact and interfere with PD-L1+ CLL leukemic B-cells. The number of CD8+ and CD4+ TLs are higher in CLL patients than in healthy donors, with an increase in effector TL number and a decrease in naive TLs. IFNγ production by TLs enhances PD-L1 expression. However, when PD-1 and PD-L1 interact, there is a significant decrease in IL-4 and IFNγ production by CD4+ and CD8+ TLs, respectively, creating a negative feedback loop, and a significant increase in the proportion of CD4+ CD25+ FOXP3 + CTLA-4+ Tregs in CLL patients. TGF-β and IL-10 are overexpressed by the CD4+ TL and Tregs and play an important role in their inhibitory function (106); IFNγ, Interferon Gamma; IL-4, Interleukine 4; IL-10, Interleukine 10; PD-1, Programmed Death 1; PD-L1, Programmed Death Ligand 1; TGF-β, Transforming Growth Factor Beta; TIL, Tumor-infiltrating Lymphocyte; TL, T Lymphocyte; Tregs, Regulatory T Lymphocytes.