CD154 on the surface of CD4+CD25+ regulatory T cells contributes to skin transplant tolerance.
BACKGROUND
It is known that the infusion of whole blood from donors (donor-specific transfusion) into recipients combined with anti-CD154 therapy can prolong allograft survival. It has generally been agreed that the effectiveness of anti-CD154 therapy is caused by the inactivation of alloreactive CD4+ and CD8+ effector T cells. The recent literature has implicated CD4+CD25+ regulatory T cells in the suppression of autoimmunity and graft rejection, and we therefore examined whether CD154 blockade is effective because of its blockade of inflammatory T-cell activation or because of a direct impact on the regulatory T cells.


METHODS
RAG(-/-) mice were adoptively transfused with CD4+ T cells or a subset of the population (CD4+CD25+ or CD4+CD25- T cells) alone or in combination with donor-specific transfusion and anti-CD154 and given an allo-skin transplant. The longevity of the transplant was determined over time. CD154(-/-)CD4+ T cells were used to assess the importance of CD154 in graft rejection and acceptance.


RESULTS
CD154 blockade (or loss of CD154) on CD4+CD25+ regulatory T cells enhanced their immunosuppressive activities and was a contributing factor to anti-CD154-induced immune suppression in vivo. In a model of allograft tolerance, suppression was elicited by antigen and anti-CD154 or antigen alone if the CD4+CD25+ regulatory T cells were deficient in CD154 expression.


CONCLUSIONS
Neutralizing the function of CD154 on regulatory T cells upon antigen exposure induces heightened levels of suppressive activities and is likely a contributing factor to the long-lived therapeutic effects of anti-CD154 treatment.
Jarvinen
Lamis Z
LZ
Department of Microbiology and Immunology, Dartmouth Hitchcock Medical Center, Dartmouth Medical School, Lebanon, New Hampshire 03756, USA.
Blazar
Bruce R
BR
Adeyi
Oyedele A
OA
Strom
Terry B
TB
Noelle
Randolph J
RJ
D019264:Adoptive Transfer; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D023201:CD40 Ligand / Q000276:immunology*; D006084:Graft Rejection / Q000276:immunology*; D006085:Graft Survival / Q000276:immunology*; D018398:Homeodomain Proteins / Q000235:genetics; D007108:Immune Tolerance; D017710:Lymphocyte Transfusion; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016038:Skin Transplantation / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D013997:Time Factors; D014184:Transplantation, Homologous / Q000276:immunology
D018398:Homeodomain Proteins; C064658:RAG-1 protein; D023201:CD40 Ligand