Significant Differences in Antigen-Induced Transendothelial Migration of Human CD8 and CD4 T Effector Memory Cells

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Abstract

Objective—

Circulating human T effector memory cell (TEM) recognition of nonself MHC (major histocompatibility complex) molecules on allograft endothelial cells can initiate graft rejection despite elimination of professional antigen-presenting cells necessary for naive T-cell activation. Our previous studies of CD4 TEM have established that engagement of the T-cell receptor not only activates T cells but also triggers transendothelial migration (TEM) by a process that is distinct from that induced by activating chemokine receptors on T cells, being slower, requiring microtubule-organizing center–directed cytolytic granule polarization to and release from the leading edge of the T cell, and requiring engagement of proteins of the endothelial cell lateral border recycling compartment. Although CD4 TEM may contribute to acute allograft rejection, the primary effectors are alloreactive CD8 TEM. Whether and how T-cell receptor engagement affects TEM of human CD8 TEM is unknown.

Approach and Results—

We modeled TEM of CD8 TEM across cultured human microvascular endothelial cells engineered to present superantigen under conditions of venular shear stress in vitro in a flow chamber. Here, we report that T-cell receptor engagement can also induce TEM of this population that similarly differs from chemokine receptor–driven TEM with regard to kinetics, morphological manifestations, and microtubule-organizing center dynamics as with CD4 TEM. However, CD8 TEM do not require either cytolytic granule release or interactions with proteins of the lateral border recycling compartment.

Conclusions—

These results imply that therapeutic strategies designed to inhibit T-cell receptor–driven recruitment based on targeting granule release or components of the lateral border recycling compartment will not affect CD8 TEM and are unlikely to block acute rejection in the clinic.

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