Memory T Cells and Their Costimulators in Human Allograft Injury

Abstract

Both CD4+ and CD8+ human memory but not naive T cells respond to allogeneic human dermal microvascular endothelial cells (HDMEC) in vitro by secreting cytokines and by proliferating. Several recently identified costimulators, namely, 4-1BB ligand, ICOS ligand, and OX40 ligand, are up-regulated on cultured HDMEC in response to TNF or coculture with allogeneic T cells. Blockade of these costimulators each partially reduces IFN-γ and IL-2 secretion and proliferation of previously resting memory T cells. The effects of these costimulators are overlapping but not identical. Memory but not naive T cells are the principal effectors of microvascular injury in human skin allografts following adoptive transfer into immunodeficient mice. Furthermore, blocking 4-1BB ligand, ICOS ligand, or OX40 ligand in this model reduces human skin allograft injury and T cell effector molecule expression. These data demonstrate that human memory T cells respond to microvascular endothelial cells and can injure allografts in vivo without priming. Furthermore, several recently described costimulators contribute to these processes.

IL-1α and IL-1β Are Endogenous Mediators Linking Cell Injury to the Adaptive Alloimmune Response

“…Given that these two cell types are in frequent contact in an allograft, the EC-T cell interaction is likely to be important in human allogeneic responses in vivo, especially those that lead to graft arteriosclerosis (1). Second, this model produces selective activation of memory T cells (62). Alloreactive memory CD4 ϩ T cells, which are difficult to study in murine models, constitute a considerable portion of the total human alloreactive T cell pool and are important mediators of allograft rejection (63,64).…”

Human endothelial cells generate Th17 and regulatory T cells under inflammatory conditions

“…HMEC-1 was provided by A. Kesikli (University of Regensburg, Germany) and used between passages eight and 15 (33). Primary ECs (i.e., HDMECs; Lonza) were used between passages three and six (34,35).…”

Interferon-γ Axis in Graft Arteriosclerosis

“…In culture, human ECs can directly present their MHC molecules to allogeneic CD4 ϩ and CD8 ϩ T cells, effectively activating cytokine elaboration and proliferation from resting memory T cells. 45 Murine ECs activate CD8 ϩ but not CD4 ϩ effector T cells, even when they are induced to express class II MHC molecules in response to IFN-␥. 46,47 Instead, IFN-␥-treated murine ECs may predominantly activate CD4 ϩ CD25 ϩ regulatory T cells, 48 a finding we have not been able to replicate with human ECs (J.S.…”