1159: Expanded Cytotoxic CD8+ T Cell Clones Characterize the Blood of Inclusion Body Myositis Patients

Miriam Fein¹, Laura Donlin¹, David Fernandez¹ and Lorien Shakib², ¹Hospital for Special Surgery, New York, NY, ²Weill Cornell Medicine, New York, NY

Background/Purpose: Inclusion body myositis (IBM) is an inflammatory myopathy, characterized by CD8+ T cell infiltration of muscle and patients present with progressive muscle weakness and atrophy, leading to disability due to no FDA-approved therapies. Patients with IBM have been noted to frequently exhibit aberrant expansion of circulating CD8+ T cells, even satisfying classification criteria for T cell large granular lymphocytic leukemia (T-LGL) in >50% of cases, in one study. However, high-resolution profiling of the transcriptome and TCR repertoire in IBM are lacking.

We aim to evaluate the TCR repertoire of circulatory CD8+ T cells, allowing us to simultaneously define the transcriptomes of expanded and non-expanded clonotypes in blood of IBM patients.

Methods: 12 IBM patients and 8 age-matched healthy controls were sorted for non-naïve CD8+ T cells by flow cytometry. Single-cell RNA and TCR sequencing was performed to profile the whole gene expression, coupled with paired TCRa and TCRb chains, at single-cell resolution. Additional markers during flow cytometry allowed for further identification of aberrant populations in IBM compared to age-matched healthy controls.

Results: Our results found IBM CD8+ T cell were highly expanded compared to age-matched healthy controls. These CD8+ T cells were identified in both the broad non-naïve T cell population, as well as the specific CD8+ CD57+ T cell subset. Enrichment of T-LGL leukemia genes, in addition to CD8+ effector function, cytotoxicity and inflammatory chemokines and cytokines were found in expanded clonotypes, with a higher gene expression found in hyperexpanded clones compared to minimally expanded clonotypes. Absence of common TCR clonotypes between patients in IBM was found, a pattern also seen in T-LGL leukemia. GSEA analysis also confirmed a downregulation of cell apoptosis processes in hyperexpanded clonotypes, a feature of T-LGL leukemia clones.

Conclusion: Significant clonal expansion of CD8+ T cells in the blood was found in our IBM cohort compared to our age-matched healthy controls. Additionally, these hyperexpanded clonotypes have elevated cytotoxic and T cell activation genes in comparison to their minimally expanded counterparts. These results highlight how the blood compartment of IBM, a progressive muscle disease, is important in IBM and how future studies and therapies should be targeting these aberrant CD8+ T cell clones.


M. Fein: None; L. Donlin: Bristol-Myers Squibb(BMS), 2, Stryker, 2; D. Fernandez: None; L. Shakib: None.