LAG3 Is Expressed on Muscle-Infiltrating Cytotoxic T Cells, but Scarce on Circulating T Cells, in Patients With Inclusion Body Myositis.

Abstract

Introduction/aims: Selective depletion of muscle-infiltrating pathogenic T cells is a promising therapeutic approach for inclusion body myositis (IBM), but no ideal cell surface antigen that is selectively expressed on these cells has been identified. LAG3 is expressed on highly differentiated, recently activated T cells, but detailed expression profiles in IBM patients have not been reported. This study was intended to bridge this research gap.

Methods: First, biobank-stored skeletal muscle tissue samples (biceps or quadriceps) of six IBM patients, which had been biopsied for diagnosis, were used for immunohistochemistry (IHC) for T-cell antigens including LAG3 and CD244, a surface marker of late-differentiated lymphocytes. Next, eight IBM patients were enrolled, and fluorescence-activated cell sorting (FACS) was performed on their blood to count the LAG3-expressing cells. Muscle magnetic resonance imaging (MRI) and whole-blood microarrays were also performed.

Results: Upon analyzing LAG3 expression on 41-128 CD3⁺ lymphocytes and 11-86 CD244⁺ lymphocytes counted in the regions of interest (ROIs) for each biobank-stored sample, their positivity rates were 19.3%-48.0% and 41.7%-75.6%, respectively. In contrast, notably few LAG3-expressing cells were present in the blood. Both CD8⁺LAG3⁺ and CD8^-LAG3⁺ cells constituted less than 0.1% of total T cells, although muscle MRI and blood microarray, showing upregulation of the proinflammatory genes GBP1 and GBP5, revealed both myositis and systemic inflammatory conditions in these patients.

Discussion: Agents that deplete LAG3⁺ lymphocytes, such as anti-LAG3 antibody that induces antibody-dependent cell cytotoxicity, are potential drug candidates with a favorable efficacy/safety balance for treating IBM.