Skin-homing CD8 + T cells preferentially express GPI-anchored peptidase inhibitor 16, an inhibitor of cathepsin K.

This study sought to identify novel CD8(+) T cell homing markers by studying acute graft versus host disease (aGvHD), typically involving increased T cell homing to the skin and gut. FACS-sorted skin-homing (CD8 beta(+)/CLA(+)), gut-homing (CD8 beta(+)/integrin beta 7(+)), and reference (CD8 beta(+)/CLA(-)/integrin beta 7(-)) T cells were compared in patients affected by cutaneous and/or gastrointestinal aGVHD. Microarray analysis, qPCR, and flow cytometry revealed increased expression of peptidase inhibitor 16 (PI16) in skin-homing CD8(+) T cells. Robust association of PI16 with skin homing was confirmed in all types of aGvHD and in healthy controls, too. PI16 was not observed on CLA(+) leukocytes other than T cells. Induction of PI16 expression on skin-homing T cells occurred independently of vitamin D3. Among skin-homing T cells, PI16 expression was most pronounced in memory-like CD45RO(+)/CD127(+)/CD25(+)/CD69(-)/granzyme B- cells. PI16 was confined to the plasma membrane, was GPI-anchored, and was lost upon restimulation of memory CD8(+) T cells. Loss of PI16 occurred by downregulation of PI16 transcription, and not by Phospholipase C (PLC)- or Angiotensin-converting enzyme (ACE)-mediated shedding, or by protein recycling. Inhibitor screening and pull-down experiments confirmed that PI16 inhibits cathepsin K, but may not bind to other skin proteases. These data link PI16 to skin-homing CD8(+) T cells, and raise the possibility that PI16 may regulate cutaneous cathepsin K.