New differentiation pathway for double-negative regulatory T cells that regulates the magnitude of immune responses.
Recent studies have demonstrated that in peripheral lymphoid tissues of normal mice and healthy humans, 1% to 5% of alphabeta T-cell receptor-positive (TCR(+)) T cells are CD4(-)CD8(-) (double-negative [DN]) T cells, capable of down-regulating immune responses. However, the origin and developmental pathway of DN T cells is still not clear. In this study, by monitoring CD4 expression during T-cell proliferation and differentiation, we identified a new differentiation pathway for the conversion of CD4(+) T cells to DN regulatory T cells. We showed that the converted DN T cells retained a stable phenotype after restimulation and that furthermore, the disappearance of cell-surface CD4 molecules on converted DN T cells was a result of CD4 gene silencing. The converted DN T cells were resistant to activation-induced cell death (AICD) and expressed a unique set of cell-surface markers and gene profiles. These cells were highly potent in suppressing alloimmune responses both in vitro and in vivo in an antigen-specific manner. Perforin was highly expressed by the converted DN regulatory T cells and played a role in DN T-cell-mediated suppression. Our findings thus identify a new differentiation pathway for DN regulatory T cells and uncover a new intrinsic homeostatic mechanism that regulates the magnitude of immune responses. This pathway provides a novel, cell-based, therapeutic approach for preventing allograft rejection.
Zhang
Dong
D
Transplantation Research Center, Beth Israel Deaconess Medical Center, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.
Yang
Wei
W
Degauque
Nicolas
N
Tian
Yan
Y
Mikita
Allison
A
Zheng
Xin Xiao
XX
D000818:Animals; D015704:CD4 Antigens / Q000096:biosynthesis / Q000276:immunology*; D016827:CD8 Antigens / Q000096:biosynthesis / Q000378:metabolism; D016923:Cell Death / Q000276:immunology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D049109:Cell Proliferation; D020868:Gene Silencing / Q000276:immunology*; D006706:Homeostasis / Q000276:immunology; D007519:Isoantigens / Q000276:immunology; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins / Q000096:biosynthesis / Q000276:immunology; D016693:Receptors, Antigen, T-Cell, alpha-beta; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism*; D014184:Transplantation, Homologous
D015704:CD4 Antigens; D016827:CD8 Antigens; D007519:Isoantigens; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D016693:Receptors, Antigen, T-Cell, alpha-beta; D054353:Perforin