P.200 - PD1 and PDL2 axis confers T cell exhaustion in anti-SRP+ and anti-HMGCR+ myopathies

Abstract

Exposure to persistent antigen as in Immune-mediated necrotizing myopathies (IMNM) may lead to defective T cell function called ‘exhaustion’, which is crucially controlled by programmed cell death protein 1 (PD1) and its cognate ligands PD1L/PD2L. These molecules have recently been successfully used as immune checkpoint blockers in certain cancers. However, therapy with these may lead to increased autoimmune responses with development of e.g. myocarditis or myositis, pointing to relevance of this pathway in muscle inflammation. We have previously shown, that T cells in IMNM lack robust cytotoxicity. Here, we analyze T cell exhaustion in skeletal muscle biopsies from IMNM with anti-SRP or anti-HMGCR antibodies, by exploring the role of PD1-PD1L/PD2L. Muscle biopsies from IMNM patients were analyzed by immunostaining and immunofluorescence as well as by qPCR. CD3+ and CD8+T cells in IMNM patients' biopsies are largely PD1 positive, while a number of CD68+ macrophages are PD1L positive. The sarcolemma of myofibers is PD2L+ and co-localizes with MHC class I. Also CD68+ macrophages co-localize with PD2L. Senescent CD57+ T cells are detectable in Inclusion body myositis, while they are not present in IMNM biopsies. These data show presence of exhausted PD1+ T cells in IMNM skeletal muscles, possibly linked to persistent auto-antigen exposure. T cell exhaustion in IMNM is mediated via PD1 - PD2L preferentially, and may explain defective innate immunity in IMNM. We further highlight that senescence and exhaustion of T cells are unrelated in IMNM.