Observational support for an immunoregulatory role of CD3+CD4+CD25+IFN-γ+ blood lymphocytes in kidney transplant recipients with good long-term graft outcome

There is evidence that interferon-gamma (IFN-gamma)-dependent interactions of dendritic cell (DC), T regulatory (Treg), and T suppressor (Ts) subpopulations contribute to allograft acceptance. We measured DC subsets, CD3(+)CD4(+)CD25(+) (Treg phenotype) and CD3(+)CD8(+)CD28(-) (Ts phenotype) peripheral blood lymphocytes (PBL) expressing Foxp3, Th1 or Th2 cytokines, peripheral T- and B-cell counts, and plasma cytokines in 33 kidney transplant recipients with a serum creatinine of <= 1.8 mg/dl and 32 recipients with a serum creatinine of >= 2.0 mg/dl more than 100 days post-transplant. Cell subsets were measured in whole blood using four-color flow cytometry. Patients with increased creatinine had less frequently detectable CD3(+)CD4(+)CD25(+)IFN-gamma(+) PBL than patients with good graft function (P = 0.017). In patients with good graft function, CD3(+)CD4(+)CD25(+)IFN-gamma(+) PBL were associated with high Foxp3(+), IL-2(+), IL-12(+), IL-4(+), and IL-10(+) CD3(+)CD4(+)CD25(+) T PBL (P < 0.001), low CD3(+)CD8(+)CD28(-)Foxp3(+) (P = 0.002), CD3(+)CD4(+)DR(+) (P = 0.002), CD3(+)CD8(+)DR(+) T (P = 0.005) and CD19(+) B PBL (P = 0.005), and low lineage(-)HLA-DR(+)CD11c(+)CD123(-) DC1 (P = 0.006). Patients with impaired graft function did not show these associations. Additional flow cytometric analysis confirmed strong co-expression of IFN-gamma and Foxp3 by CD4(+)CD25(+) PBL particularly in patients with good graft function. Our data support an immunoregulatory role of CD3(+)CD4(+)CD25(+)Foxp3(+)IFN-gamma(+) cells in a subgroup of transplant recipients with good graft acceptance.