Autoimmune and inflammatory diseases associated with T-cell clonal expansion

Abstract

Autoimmune and inflammatory diseases (AID) result from a breakdown of immune tolerance, often driven by T-cell dysregulation and sometimes associated with clonal T-cell expansion. While T-cell large granular lymphocyte leukemia (LGL-L) is a well-defined clonal disorder commonly associated with AID, the clinical relevance of T-cell clones of uncertain significance (T-CUS) remains unclear. We conducted a retrospective multicenter study across six French centers, including patients with persistent circulating clonal T cells associated with AID, confirmed by T-cell receptor gene rearrangement. T-cell clones ≥ 0.5 × 10⁹/L, or low-count clones (<0.5 × 10⁹/L) associated with rheumatoid arthritis, unexplained cytopenias, or compatible bone marrow infiltration, were classified as LGL-L. T-CUS was defined by exclusion in patients who did not fulfill diagnostic criteria for T-LGL leukemia. Eighty-three patients were included (44 LGL-L and 39 T-CUS). LGL-L patients predominantly exhibited a CD8⁺ phenotype (66%) and STAT3 mutations (54%), and were more frequently associated with rheumatoid arthritis (41% vs 0%, p<0.0001) and neutropenia (52% vs 5%, p<0.0001), compared to patients with T-CUS. Granulomatous diseases were more common in the T-CUS group (28% vs 5%, p<0.01), which also displayed a broader and more heterogeneous autoimmune spectrum and a higher frequency of TET2 mutations (27% vs 0%, p<0.01). Response to T-cell targeted therapy was similar between the two groups. Overall, these findings indicate that T-cell clonality in the context of AID encompasses heterogeneous entities, ranging from reactive immune phenomena to grey-zone clones sharing features with LGL-L, supporting an integrated clinical, immunophenotypic, and molecular approach to patient management.