Fig. 1.

a Cross-linking of HLA I on the surface of endothelial and smooth muscle cells activates intracellular signaling programs that promote the mechanisms of graft injury. Intracellular calcium is released in endothelium, which triggers exocytosis of Weibel-Palade body (WPb) vesicles containing P-selectin. Rapid upregulation of P-selectin at the cell surface is sufficient to support adhesion of neutrophils, monocytes, and platelets, which likely contributes to the predominance of intragraft myeloid cells, such as CD68+ macrophages and neutrophils, during antibody-mediated rejection. HLA signaling also promotes activation of FAK, which facilitates formation of focal adhesions, and activation of RhoA, mTOR, and ERK, which act on the actin cytoskeleton to stimulate stress fibers. Stress fiber formation is dramatic and extends across the cell. mTOR and ERK are also key regulators of proteins involved in translation, S6 kinase (S6K) and S6 ribosomal protein (S6RP), and of cell growth. Activation of the PI3K/Akt axis causes upregulation of pro-survival proteins. Together, proliferative, survival, and migratory signaling likely contributes to chronic vascular rejection and intimal hyperplasia. b Schematic diagram of HLA binding in trans to receptors on opposing cells, such as the TCR on T cells, and of HLA association in cis with tetraspanins and integrins on the same cell. Trans interactions are likely the physiologically relevant mechanisms of HLA cross-linking that leads to reverse signaling into the cell, pathways which become hijacked and inappropriately activated by bivalent alloantibody during antibody-mediated rejection. Associations in cis are required for HLA, which has no known signaling motifs, to transduce signaling through coreceptors, such as integrin β4 in endothelial cells