Chemokine gradients spare graft endothelium from CD8+ T cell–mediated injury during allograft rejection
Scott M. Krummey, Jonathan S. Bromberg
Scott M. Krummey, Jonathan S. Bromberg
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Commentary

Chemokine gradients spare graft endothelium from CD8+ T cell–mediated injury during allograft rejection

Abstract

T cell–mediated rejection (TCMR) develops after alloantigen-primed T cells migrate into an allograft to cause tissue damage. In contrast to antibody-mediated rejection, which creates lesions in the graft vasculature, injury to the graft vasculature is often limited during TCMR. In this issue of the JCI, Barba et al. investigated the mechanism by which the endothelium is spared from harm caused by graft-infiltrating CD8+ T cells. Endothelial cell protection was due to cell-extrinsic chemokine variations in the environment, rather than cell-intrinsic differences between endothelial and interstitial cells. The CXCL12 gradient in particular facilitated CD8+ T cell movement through the endothelial layer into the graft parenchyma. These findings suggest that targeting the CXCL12 pathway may prevent or alleviate TCMR.

Authors

Scott M. Krummey, Jonathan S. Bromberg

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Figure 1

The CXCL12 gradient enables CD8+ T cells to bypass the allograft endothelial layer and mediate rejection.

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The CXCL12 gradient enables CD8+ T cells to bypass the allograft endothe...
Alloantigen-specific CD8+ T cells are primed in the secondary lymphoid tissue and travel via the bloodstream to the allograft. In the graft vasculature, CD8+ T cells bind to cognate peptide-HLA complexes and adhesion receptors, including integrins, selectins, and chemokine receptors, and extravasate into the graft parenchyma. Despite the presence of cognate alloantigen, the migration of alloantigen-specific CD8+ T cells leaves the donor endothelial layer largely intact. Evidence from Barba et al. (11) suggests that alloantigen-expressing endothelial cells did not have a cell-intrinsic resistance to CD8+ T cell–mediated cytotoxicity. Rather, chemokine gradients within the allograft, such as CXCL12, promoted CD8+ T cell migration through the endothelial layer and into the graft interstitium, where graft epithelial cells are susceptible to cytotoxic injury.