Identification of Regulatory T Cells in Tolerated Allografts

TLDR

Transplantation tolerance induced by nondepleting monoclonal antibodies establishes a robust peripheral dominant tolerance mediated by regulatory CD4⁺ T cells that can be isolated from tolerant animals’ spleens. The study aimed to determine whether extra‑lymphoid sites, specifically tolerated skin allografts and normal skin, harbor regulatory T cells. Tolerated skin grafts were retransplanted onto T‑cell–depleted hosts, allowing graft‑infiltrating T cells to exit the graft and recolonize the new host. Colonizing T cells from the retransplanted grafts contain regulatory members that prevent nontolerant lymphocytes from rejecting fresh skin allografts while permitting third‑party rejection, demonstrating that regulatory T cells persist at the transplant site and actively suppress rejection beyond secondary lymphoid tissue.

Abstract

Induction of transplantation tolerance with certain therapeutic nondepleting monoclonal antibodies can lead to a robust state of peripheral “dominant” tolerance. Regulatory CD4+ T cells, which mediate this form of “dominant” tolerance, can be isolated from spleens of tolerant animals. To determine whether there were any extra-lymphoid sites that might harbor regulatory T cells we sought their presence in tolerated skin allografts and in normal skin. When tolerated skin grafts are retransplanted onto T cell–depleted hosts, graft-infiltrating T cells exit the graft and recolonize the new host. These colonizing T cells can be shown to contain members with regulatory function, as they can prevent nontolerant lymphocytes from rejecting fresh skin allografts, without hindrance of rejection of third party skin. Our results suggest that T cell suppression of graft rejection is an active process that operates beyond secondary lymphoid tissue, and involves the persistent presence of regulatory T cells at the site of the tolerated transplant.