Effects of Human Umbilical Cord Blood Regulatory T Cells on Effector CD8+ T Cell Differentiation

CD8+ T cells are crucial for host defense against virus and tumor cells. Upon antigen recognition, CD8+ T cells acquire effector functions. CD4+CD25+ regulatory T cell (Treg) has been known to suppress the CD8+ T cell‐mediated anti‐tumor immune responses. The mechanisms by which Treg suppresses the CD8+ T cell‐mediated effector responses remain unclear. In contrast, the signal through the NKG2D receptor promotes CD8+ T cell effector responses as an activating co‐stimulatory receptor. We investigated whether Treg and NKG2D counteract the effector CD8+ T cell activity using naïve CD8+ T cells isolated from human umbilical cord blood (CB). Induction of granzyme B is a hallmark of CD8+ T cell effector differentiation. By co‐culturing Treg with CD8+ T cells followed by flow analysis, we found that Treg did not suppress but promoted induction of granzyme B. NKG2D expression has been known to be downregulated by tumor cell‐derived ligand binding in cancer patients. Thus, Treg may inhibit induction of NKG2D expression in the CD8+ T cells. We mimicked the ligand‐induced downregulation of NKG2D by culturing the CD8+ T cells on anti‐NKG2D coated plates. Downregulated NKG2D expression was gradually restored. We examined whether Treg affected the restoration of NKG2D on the CD8+ T cells by culturing anti‐NKG2D on CD8+ T cells with or without Treg. Treg increased NKG2D expression as it did granzyme B expression. Thus, Treg isolated from CB enhanced induction of granzyme B and NKG2D expression in CD8+ T cells. Supported in part by NIH R25 GM067592‐02 and P01 AI56097‐02S1.