CCR5 Is required for regulation of alloreactive T-cell responses to single class II MHC-mismatched murine cardiac grafts

Abstract

The effector CD4 T-cell response in wild-type C57BL/6 recipients of single class II MHC-disparate B6.H-2bm12 cardiac allografts is restricted by CD4+CD25+ regulatory T cells (Tregs) resulting in long-term allograft survival. To investigate the role chemokine receptors might play in Treg function, this study tested the requirement for CCR5 on Tregs to suppress the alloimmune response in C57BL/6 recipients of B6.H-2bm12 cardiac allografts. In contrast to the long-term survival of B6.H-2 bm12 allografts in wild-type recipients (>100 days), the allografts were acutely rejected within 25 days in CCR5-/- recipients with intense infiltration of CD4 T cells. Numbers and duration of donor-reactive CD4 T cells producing IFN-γ and IL-4 were markedly increased in spleens of B6.CCR5-/- versus wild-type recipients. Wild-type and B6.CCR5-/- mice had equivalent numbers of splenic FoxP3+ Tregs before and following transplantation, and these Tregs were equivalently suppressive in vitro. However, diminished numbers of FoxP3+ Tregs infiltrated B6.H-2bm12 allografts in B6.CCR5-/- recipients. Adoptive transfer of wild-type, but not CCR5-deficient, CD4+CD25+ Tregs to CCR5-/- recipients restored long-term survival of B6.H-2bm12 cardiac grafts. Collectively, these results indicate that CCR5 expression is required for the regulatory functions of Tregs that restrict alloreactive CD4 T-cell responses to single class II MHC-mismatched cardiac allografts. © 2009 The American Society of Transplantation and the American Society of Transplant Surgeons.