T Cell Receptor Repertoire Landscape Mapping: A Novel Paradigm for T Cell Mediated Autoimmune Disorders Based on Deep Vβ Chain Sequencing

• Published in: Blood 2011-11, Vol.118 (21), p.1341-1341
• Main Authors: Clemente, Michael J, Przychodzen, Bartlomiej, Makishima, Hideki, Afable, Manuel G, Lichtin, Alan E., Maciejewski, Jaroslaw P.
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V118.21.1341.1341

Abstract 1341 T cell large granular lymphocytosis (T-LGL), a chronic lymphoproliferation of cytotoxic T cells (CTL) is often associated with lineage-restricted cytopenias. CTL-mediated inhibition of hematopoiesis in T-LGL is, in principle, similar to other T cell-mediated bone marrow failure syndromes. Variation in the CTL target spectrum could explain the lineage-restricted cytopenias in T-LGL and pancytopenia in aplastic anemia (AA). Regardless of effector mechanisms, T-LGL can serve as a simplified, monoclonal model of otherwise polyclonal CTL-mediated AA. The study of TCR Vβ clonotypes has the potential to reveal the nature/derivation of antigenic targets. It is possible that clonal specificity is private, inherently unique, and thus suggestive of the existence of neo-antigens or unique exogenous antigenic drivers. In an alternative scenario, one could expect a high degree of clonal sharing between T-LGL patients who have a similar hematologic presentation and immunogenetic background. Finally, finding of expanded T-LGL clonotypes in controls could point toward autoantigens and breach of tolerance in T-LGL or possibly an inability to maintain viral defense. Consequently, the study of the TCR repertoire may reveal unique patterns allowing for classification of immune-mediated disease. In the past, molecular analysis of the T cell repertoire allowed only a quantitatively limited insight into the clonotypic spectrum. With the advent of next generation sequencing (NGS), the clonotypic repertoire can now be analyzed at an incredible depth. Beginning with a cohort of 143 patients with T-LGL leukemia, we observed a marked increase in clone size as assessed by Vβ flow cytometry in patients with HLA-B7 (p