Restrictions in the T-cell repertoire of chronic lymphocytic leukemia: high-throughput immunoprofiling supports selection by shared antigenic elements

Immunoglobulin (IG) gene repertoire restrictions strongly support antigen selection in the pathogenesis of chronic lymphocytic leukemia (CLL). Given the emerging multifarious interactions between CLL and bystander T cells, we sought to determine whether antigen(s) are also selecting T cells in CLL. We performed a large-scale, next-generation sequencing (NGS) study of the T-cell repertoire, focusing on major stereotyped subsets representing CLL subgroups with undisputed antigenic drive, but also included patients carrying non-subset IG rearrangements to seek for T-cell immunogenetic signatures ubiquitous in CLL. Considering the inherent limitations of NGS, we deployed bioinformatics algorithms for qualitative curation of T-cell receptor rearrangements, and included multiple types of controls. Overall, we document the clonal architecture of the T-cell repertoire in CLL. These T-cell clones persist and further expand overtime, and can be shared by different patients, most especially patients belonging to the same stereotyped subset. Notably, these shared clonotypes appear to be disease-specific, as they are found in neither public databases nor healthy controls. Altogether, these findings indicate that antigen drive likely underlies T-cell expansions in CLL and may be acting in a CLL subset-specific context. Whether these are the same antigens interacting with the malignant clone or tumor-derived antigens remains to be elucidated

Comparative analysis of predicted HLA binding of immunoglobulin idiotype sequences indicates T cell-mediated immunosurveillance in follicular lymphoma

Active immunization with the idiotype of follicular lymphoma induces tumor-specific immunity. T cells induced in vivo by idiotype vaccination recognize human leukocyte antigen (HLA)-restricted hypervariable but not conserved idiotype peptides. We hypothesized that idiotype-directed T-cell immunity occurs naturally and performed a reverse immunology analysis of idiotype HLA binding in 39 follicular lymphoma patients. For every idiotype, the sum of HLA-A or -B binding scores of the 20 highest-scoring peptides was calculated for all 39 HLA types through the BIMAS algorithm. The idiotype sum score of every patient's lymphoma was compared on the respective patient's HLA type to the mean of the sum scores of the remaining 38 idiotypes. Autologous idiotypes had lower immunogenicity than allogeneicidiotypes. Differentialimmuno-genicity resided predominantly in all 3 complementarity-determining regions rather than in framework peptides. Idiotype immunogenicity was not changed by somatic hypermutation. These findings indicate T cell-mediated immunosurveillance of follicular lymphoma directed specifically against individual idiotype epitopes. (Blood. 2010; 116(10):1734-1736)Immunobiology of allogeneic stem cell transplantation and immunotherapy of hematological disease

HLA-Dependent Immune Selection Pressure on the Idiotype-Is Predominantly Driven by Somatic Hypermutation In Malignant Lymphoma but Also Modulates Vh Usage In Normal B Cells

Immunobiology of allogeneic stem cell transplantation and immunotherapy of hematological disease

Evidence for idiotype-directed immunosurveillance is restricted to follicular lymphoma and attributable to somatic hypermutation

Immunobiology of allogeneic stem cell transplantation and immunotherapy of hematological disease

The role of activation induced deaminase-mediated somatic hypermutation and subsequent subclone evolution for pathophysiology of follicular lymphomas

Development and application of statistical models for medical scientific researc

Chronic lymphocytic leukaemia is driven by antigen-independent cell-autonomous signalling

Immunobiology of allogeneic stem cell transplantation and immunotherapy of hematological disease