0984: Interleukin-21 as a driver of CD8 T cell tissue resident memory and pathogenesis in dermatomyositis

Background/Purpose: Dermatomyositis is an autoimmune disease characterized by skin and muscle pathology and can feature significant morbidity and mortality from interstitial lung disease (ILD). Dermatomyositis is traditionally considered an antibody-mediated disease driven by pathogenic CD4 T cells and B cells as there are multiple myositis specific antibodies identified in dermatomyositis. These myositis-specific antibodies can have significant differences in disease progression. CD4 T cell-derived IL-21, a cytokine best known for its stimulation of B cells during the germinal center response, may be a driver of dermatomyositis. While IL-21 likely plays a role in stimulating myositis specific antibody production, IL-21 has also been identified as a CD4 T cell-derived driver of CD8 T cell differentiation to tissue resident memory cells (T_RM). T_RM are named for their abilities to be maintained independent of the circulation in non-lymphoid tissues and rapidly release effector molecules during antigen re-encounter which we hypothesized could be an important step in the pathogenesis of dermatomyositis.

Methods: We performed immunofluorescence labeling for CD4, CD8, and IL-21 on skin biopsy samples from dermatomyositis patents. We also obtained single-cell RNAseq data from the lungs of a patient with MDA5+ dermatomyositis and subsequent ILD. Using the RNAseq data, we analyzed the CD8 T cells for IL-21 receptor expression and gene expression profiles of tissue resident memory.

Results: We show that IL-21 is present in active dermatomyositis skin lesions and that IL-21 is present in areas with high CD4 T cell and CD8 T cell infiltrates. We also show with the single-cell RNAseq data that lung CD8 T cells highly express the IL-21 receptor compared to CD8 T cells from the lungs of controls. Gene set enrichment analyses showed significant enhancement in the expression of T_RM genes in the CD8 T cells from the dermatomyositis lung.

Conclusion: These data suggest IL-21 could be an important, understudied driver of ILD in dermatomyositis, and a potential therapeutic target. Specifically, IL-21 may act on CD8 T cells to drive differentiation into long-lived T_RM in the tissues of dermatomyositis, likely contributing to tissue damage and clinical pathology.