School of Medicine: Recent submissions
Now showing items 1-20 of 2438
-
CD45.1/CD45.2 Congenic Markers Induce a Selective Bias for CD8+ T Cells During Adoptive Lymphocyte Proliferation in Lymphocytopenia MiceCD45.1/CD45.2 congenic markers have been frequently used to track hematopoietic lineage differentiation following hematopoietic stem and progenitor cell (HPSC) transplantation. However, several studies suggest that a bias exists in CD45.1 versus CD45.2 hematopoietic cell reconstitution from the transplanted HPSCs. Meanwhile, no definitive comparison has been reported for mature immune cells as to whether the CD45.1/CD45.2 disparity can skew immune cell response. In this study using lymphocytopenia Rag1-/- CD45.2 mice as hosts, we assessed the proliferative potential of CD45.1 versus CD45.2 lymphocytes following adoptive transfer of mature T and B cells harvested from the spleens of CD45.1 and CD45.2 mice. We have found that a selective bias for CD8+ T cells in that CD45.1 CD8+ T cells showed significantly higher proliferation and higher expression of PD-1 compared CD45.2 CD8+ T cells in the Rag1-/- CD45.2 hosts. This bias is likely due to MHC-I restricted allogeneic stimulation as CD45.1 versus CD45.2 CD4+ T cells and CD19+ B cells contained the same graft as CD8+ T cells showed equivalent proliferation. These results suggest that CD45.1/CD45.2 markers induce an alloreactive response specific to CD8+ T cells, and therefore call for caution for using them.
-
PD-L1 couples with LTβR signaling to accelerate tumor growth and metastasisTregs accumulate in the tumor microenvironment, constrain anti-tumor immunity, and are critical targets for anti-tumor strategies. We previously showed that Tregs use surface lymphotoxin (LTαβ) and PD-1 to signal LTβR and PD-L1 on lymphatic endothelial cells (LECs), thereby promoting Treg lymphatic transendothelial migration (TEM)1,2 . Most tumor cells express LTβR and PD-L1, yet tumor interactions with LTαβ and PD-1 on Tregs are poorly studied. Here we investigate whether PD-L1 couples with LTβR signaling on tumors or LECs to regulate cell migration and tumor metastasis. Results show PD-L1 bound to LTβR in resting B16F10 melanoma cell and PD-L1 deficiency enhanced LTβR expression and apoptosis. Blocking LTβR-nonclassical NFB-NIK signaling increased melanoma PD-L1 expression but decreased tumor TEM. RNASeq analysis of B16F10 revealed that genes regulated by LTβR nonclassical NFB signaling were increased by PD-L1 depletion. LTβR activation promoted B16F10 TEM, and PD-L1 deficiency abolished the enhancement, indicating PDL1 is required for LTbR signaling mediated tumor TEM. Tregs but not effector T cells can directly activate B16F10 LTbR-nonclassical NFB signaling, suggesting a critical role of Treg LT-tumor LTbR signaling for tumor metastasis. In vivo, PD-L1 blockade combined with LTβR classical or nonclassical NFB blocking peptides inhibited tumor growth and metastases, and enhanced host survival. Overall, PD-L1 couples with LTβR-nonclassical NFB signaling to regulate tumor growth and migration. Blocking both arms of tumor LTβR-NFκB-signaling enhanced immune checkpoint blockade efficacy and tumor bearing mouse survival. These observations provide a rational strategy to modulate Treg activities to prevent tumor spread.
