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

Summary

There is evidence that interferon-gamma (IFN-γ)-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-γ⁺ PBL than patients with good graft function (P = 0.017). In patients with good graft function, CD3⁺CD4⁺CD25⁺IFN-γ⁺ 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-γ 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-γ⁺ cells in a subgroup of transplant recipients with good graft acceptance.