CD4+CD25+ regulatory T cells suppress allograft rejection mediated by memory CD8+ T cells via a CD30-dependent mechanism.
CD4(+)CD25(+) regulatory T (Treg) cells suppress naive T cell responses, prevent autoimmunity, and delay allograft rejection. It is not known, however, whether Treg cells suppress allograft rejection mediated by memory T cells, as the latter mount faster and stronger immune responses than their naive counterparts. Here we show that antigen-induced, but not naive, Treg cells suppress allograft rejection mediated by memory CD8(+) T cells. Suppression was allospecific, as Treg cells induced by third-party antigens did not delay allograft rejection. In vivo and in vitro analyses revealed that the apoptosis of allospecific memory CD8(+) T cells is significantly increased in the presence of antigen-induced Treg cells, while their proliferation remains unaffected. Importantly, neither suppression of allograft rejection nor enhanced apoptosis of memory CD8(+) T cells was observed when Treg cells lacked CD30 or when CD30 ligand-CD30 interaction was blocked with anti-CD30 ligand Ab. This study therefore provides direct evidence that pathogenic memory T cells are amenable to suppression in an antigen-specific manner and identifies CD30 as a molecule that is critical for the regulation of memory T cell responses.
Dai
Zhenhua
Z
Section of Nephrology, Department of Internal Medicine, Yale University School of Medicine, New Haven CT 06520, USA. zhenhua.dai@yale.edu
Li
Qi
Q
Wang
Yinong
Y
Gao
Ge
G
Diggs
Lonnette S
LS
Tellides
George
G
Lakkis
Fadi G
FG
D000818:Animals; D000941:Antigens / Q000096:biosynthesis / Q000737:chemistry; D017209:Apoptosis; D001973:Bromodeoxyuridine / Q000494:pharmacology; D015704:CD4 Antigens / Q000096:biosynthesis; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D002455:Cell Division; D016207:Cytokines / Q000378:metabolism; D006084:Graft Rejection; D006720:Homozygote; D018960:Hyaluronan Receptors / Q000096:biosynthesis; D007156:Immunologic Memory; D016130:Immunophenotyping; D020287:In Situ Nick-End Labeling; D017730:Ki-1 Antigen / Q000096:biosynthesis*; D008024:Ligands; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis*; D013154:Spleen / Q000166:cytology; D013601:T-Lymphocytes / Q000166:cytology / Q000378:metabolism; D013997:Time Factors
D000941:Antigens; D015704:CD4 Antigens; D016207:Cytokines; D018960:Hyaluronan Receptors; D017730:Ki-1 Antigen; D008024:Ligands; D015375:Receptors, Interleukin-2; D001973:Bromodeoxyuridine