Restricted T cell receptor repertoire in CLL-like monoclonal B cell lymphocytosis and early stage CLL

Abstract

Analysis of the T cell receptor (TR) repertoire of chronic lymphocytic leukemia-like monoclonal B cell lymphocytosis (CLL-like MBL) and early stage CLL is relevant for understanding the dynamic interaction of expanded B cell clones with bystander T cells. Here we profiled the T cell receptor β chain (TRB) repertoire of the CD4 and CD8 T cell fractions from 16 CLL-like MBL and 13 untreated, Binet stage A/Rai stage 0 CLL patients using subcloning analysis followed by Sanger sequencing. The T cell subpopulations of both MBL and early stage CLL harbored restricted TRB gene repertoire, with CD4 T cell clonal expansions whose frequency followed the numerical increase of clonal B cells. Longitudinal analysis in MBL cases revealed clonal persistence, alluding to persistent antigen stimulation. In addition, the identification of shared clonotypes among different MBL/early stage CLL cases pointed towards selection of the T cell clones by common antigenic elements. T cell clonotypes previously described in viral infections and immune disorders were also detected. Altogether, our findings evidence that antigen-mediated TR restriction occurs early in clonal evolution leading to CLL and may further increase together with B cell clonal expansion, possibly suggesting that the T cell selecting antigens are tumor-related.

Immune Dysfunctions and Immune-Based Therapeutic Interventions in Chronic Lymphocytic Leukemia

“…Although cytomegalovirus (CMV) infection has shown to induce T-cell expansion and modulate the distribution of differentiation subsets, the exhaustion observed in T cells from CLL patients resulted to be independent from CMV serostatus (82,(93)(94)(95). The progressive skew of the T-cell receptor (TCR) repertoire occurring during disease progression, may suggest a tumor-related antigen-mediated selection (96,97). In line with this observation, an oligoclonal CD8+ effector T-cell population, that expands along with CLL progression and controls disease development, was observed in both CLL patients and mice bearing a CLL-like disease (90).…”

Harnessing the Effects of BTKi on T Cells for Effective Immunotherapy against CLL

“…T-cell clonal expansion parallels the numerical increase of clonal B cells. Hence, it has been suggested that select T-cell clones expand in response to tumor-specific antigens [24]. In recent years, sequencing of the TRBV CDR3 region has been used to study the T-cell repertoire, diversity of TCR subfamilies and antigen-specific expansion of T-cell clones.…”

Engaging Cytotoxic T and NK Cells for Immunotherapy in Chronic Lymphocytic Leukemia

“…T-cell receptor (TCR) repertoires of CD4 + and CD8 + T cells in CLL show decreased diversity and skewed clonal expansion [32,33]. Expanded T-cell clones in CLL persist over time, and T-cell expansion correlates with tumor load, leading to the hypothesis that expanded T-cell clones contain tumor-specific T-cell populations [32,33].…”