Context-dependent T cell receptor gene repertoire profiles in proliferations of T large granular lymphocytes

T cell large granular lymphocyte (T-LGL) proliferations form a disease spectrum ranging from poly/oligo- to monoclonal. Boundaries within this spectrum of proliferations are not well established. T-LGL proliferations co-occur with a wide variety of other diseases ranging from auto-immune disorders, solid tumors, hematological malignancies, after solid organ and hematopoietic stem cell transplantation and can therefore arise as a consequence of a wide variety of antigenic triggers. Persistence of a dominant malignant T-LGL clone is established through continuous STAT3 activation. Utilizing NGS, we profiled a cohort of 27 well established patients with T-LGL proliferations, aimed at identifying the subclonal architecture of the T cell receptor beta (TRB) chain gene repertoire. Moreover, we searched for associations between TRB gene repertoire patterns and clinical manifestations, with the ultimate objective of discriminating between T-LGL proliferations developing in different clinical contexts and/or displaying distinct clinical presentation. Altogether, our data demonstrates that the TRB gene repertoire of patients with T-LGL proliferations is context-dependent, displaying distinct clonal architectures in different settings. Our results also highlight that there are monoclonal T-LGL cells with or without STAT3 mutations causing symptoms such as neutropenia on one end of a spectrum and reactive oligoclonal T-LGL proliferations on another. Longitudinal analysis revealed temporal clonal dynamics and showed that T-LGL cells might arise as an epiphenomenon, possibly reactive towards tumor antigens when co-occurring with other malignancies.