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

Lupsa, Nikolett and Érsek, Barbara and Horváth, Andor and Bencsik, András and Lajkó, Eszter and Silló, Pálma and Oszvald, Ádám and Wiener, Zoltán and Reményi, Péter and Mikala, Gábor and Masszi, Tamás and Buzás, Edit I. and Pós, Zoltán (2018) Skin-homing CD8+ T cells preferentially express GPI-anchored peptidase inhibitor 16, an inhibitor of cathepsin K. EUROPEAN JOURNAL OF IMMUNOLOGY. pp. 1944-1957. ISSN 0014-2980 (In Press)

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Abstract

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 skinhoming (CD8β+/CLA+), gut-homing (CD8β+/integrinβ7+), and reference (CD8β+/CLA-/integrinβ7-) T cells were compared in patients affected by cutaneous and/or gastrointestinal aGVHD. Microarray analysis, Q-PCR 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 re-stimulation of memory CD8+ T cells. Loss of PI16 occurred by down-regulation of PI16 transcription, and not by PLC- or 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.

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