Inborn errors of immunity underlie clonal T cell expansions in large granular lymphocyte leukemia

Area of Science:

• Immunology
• Genetics
• Hematology

Background:

• T cell large granular lymphocyte leukemia (T-LGLL) is a cytotoxic T lymphocyte disorder often linked to STAT3 mutations.
• While autoimmunity is suspected, paradoxical observations suggested underlying immunodeficiency in T-LGLL.

Purpose of the Study:

• To investigate if immunodeficiency traits contribute to T-LGLL pathogenesis.
• To analyze the immunogenomic landscape of T-LGLL patients for inborn errors of immunity (IEI) and somatic mutations.

Main Methods:

• Comprehensive immunogenomic profiling of 92 T-LGLL patients, including whole-exome sequencing for IEI variants and T cell drivers.
• Single-cell and bulk RNA sequencing, and TCR sequencing were used to correlate findings.
• Comparison with a large control cohort for IEI variant frequencies.

Main Results:

• 77% of T-LGLL patients exhibited lymphocytopenia and/or hypogammaglobulinemia.
• 36% of patients carried rare heterozygous variants in immune genes, with 16% having high-confidence deleterious variants associated with adult-onset IEIs.
• Patients with IEI variants showed earlier onset, lower lymphocyte counts, and increased hypogammaglobulinemia and cytopenia compared to non-carriers.

Conclusions:

• Maladaptive cytotoxic T lymphocyte expansions in T-LGLL can be linked to cryptic immunodeficiency traits.
• This research broadens the understanding of inborn errors of immunity in the context of clonal hematopoiesis and bone marrow failure.