Abstract
"Suppressor T cells'' were historically defined within the CD8(+) T-cell compartment and recent studies have highlighted several naturally occurring CD8(+)Foxp3(-) Treg populations. However, the relevance of CD8(+)Foxp3(+) T cells, which represent a minor population in both thymi and secondary lymphoid organs of nonmanipulated mice, remains unclear. We here demonstrate that de novo Foxp3 induction in peripheral CD8(+)Foxp3(-) T cells is counter-regulated by DC-mediated co-stimulation via CD80/CD86. CD8(+)Foxp3(+) T cells fail to develop in TCR-transgenic mice with Rag1(-/-) background, similar to classical CD4(+) Foxp3(+) Tregs. Notably, both naturally occurring and induced CD8(+)Foxp3(+) T cells express bona fide Treg markers including CD25, GITR, CTLA4 and CD103, and show defective IFN-gamma production upon restimulation when compared with their CD8(+)Foxp3(-) counterparts. However, utilizing DEREG transgenic mice for the isolation of Foxp3(+) cells by eGFP reporter expression, we demonstrate that induced CD8(+)Foxp3(+) T cells similar to activated CD8(+) Foxp3 T cells only mildly suppress T-cell proliferation and IFN-gamma production. We therefore categorize CD8(+)Foxp3(+) T cells as a tightly controlled population sharing certain developmental and phenotypic properties with classical CD4(+)Foxp3(+) Tregs, but lacking potent suppressive activity.