IFN-γ and IL-10 secretion by sorted T cell subsets of irreversibly rejected kidney graft-infiltrating cells (GIC) and normal PBMC was studied by ELISPOT. The low spontaneous frequency of IFN-γ-producing cells (IFN-γ-PC) was strongly increased by anti-CD3 activation within unsorted, CD3+ CD4+, and CD3+CD4- subsets of GIC and PBMC. In contrast with PBMC, IL-10-PC from GIC were at higher frequency within CD4+ cells than among CD4- ones (P<0.03). Four kidneys removed after 3.7±0.8 months showed acute vascular rejection, high frequency of activated CD4+ IL-10-PC (118±68 per 104 cells), and high percentage of anticlass II antibody reactivity (87.6±6.3%). In contrast, four patients with kidneys removed later (53.7±1.6 months, P=0.02) displayed chronic rejection with superimposed acute cellular rejection, low frequency of CD4+ IL-10-PC (7.0±3.0 per 104 cells, P=0.02), and low percentage of anti-class II antibody reactivity (12.9±6.1%, P=0.02). Thus, accelerated vascular rejection appears to be associated with preferential production of IL-10 by activated CD4+ GIC, which may act by shifting the effector arms of alloreaction toward humoral responses.