PD-1 is expressed in the thymus primarily on CD4
-CD8
- (double negative) T-cells late in the transition from double negative to double positive cells. Double negative γδ thymocytes express high levels of PD-1, and natural killer T-cells express low levels of PD-1. Moreover, interesting findings have shown that PD-L1 is expressed at high levels by activated CD4+T cells [
22]. Although PD-1 was not preferentially expressed in pro-B cells from human fetal bone marrow, treatment of isolated pro-B cells with IL-7 resulted in a dramatic increase in expression [
16,
17,
27]. PD-L1 is expressed on almost all types of lymphohematopoietic cells at varying levels and is constitutively expressed on T-cells, B-cells, macrophages and dendritic cells (DCs). This ligand is further upregulated and strongly induced by mitogenic stimulation and IFN-γ, which is reminiscent of PD-1 receptor expression [
28,
29]. Moreover, the PD-L1 splice variant expression pattern was variable in different individuals and different cellular statuses. PD-L1 expression may be regulated at the posttranscriptional level through alternative splicing, and modulation of PD-L1 isoform expression may influence the outcome of specific immune responses in peripheral tissues [
30]. The expression of PD-L1 is also detected on non-lymphoid cells e.g., endothelial cells in the heart, β cells in the pancreas, glial cells in inflamed brains and muscle cells [
31‐
35]. Moreover, PD-L1 is abundant in human carcinomas of the lung, ovary and colon and in melanoma [
36] and leukemic cells [
28,
37,
38]. The latter finding appears to be important for cancer immunotherapy.