Lack of common TCRA and TCRB clonotypes in CD8+/TCRαβ+ T-cell large granular lymphocyte leukemia: a review on the role of antigenic selection in the immunopathogenesis of CD8+ T-LGL

Y Sandberg,Y Pol,T Szczepanski,A W Langerak,W A Dik,D Tielemans,I L M Wolvers-Tettero,E J Van Gastel-Mol,M J Kallemeijn,N Darzentas,J J M Van Dongen

doi:10.1038/bcj.2013.70

Abstract

Clonal CD8+/T-cell receptor (TCR)αβ+ T-cell large granular lymphocyte (T-LGL) proliferations constitute the most common subtype of T-LGL leukemia. Although the etiology of T-LGL leukemia is largely unknown, it has been hypothesized that chronic antigenic stimulation contributes to the pathogenesis of this disorder. In the present study, we explored the association between expanded TCR-Vβ and TCR-Vα clonotypes in a cohort of 26 CD8+/TCRαβ+ T-LGL leukemia patients, in conjunction with the HLA-ABC genotype, to find indications for common antigenic stimuli. In addition, we applied purpose-built sophisticated computational tools for an in-depth evaluation of clustering of TCRβ (TCRB) complementarity determining region 3 (CDR3) amino-acid LGL clonotypes. We observed a lack of clear TCRA and TCRB CDR3 homology in CD8+/TCRαβ+ T-LGL, with only low level similarity between small numbers of cases. This is in strong contrast to the homology that is seen in CD4+/TCRαβ+ T-LGL and TCRγδ+ T-LGL and thus underlines the idea that the LGL types have different etiopathogenesis. The heterogeneity of clonal CD8+/TCRαβ+ T-LGL proliferations might in fact suggest that multiple pathogens or autoantigens are involved.

Highlights

Large granular lymphocyte (LGL) proliferations are derived from normal cytotoxic LGL cells, which comprise 10–15% of peripheral blood (PB) mononuclear cells (MNCs).[1,2,3] The majority of the normal LGL cells (85%) are of NK-cell origin, and a minority is derived from mature T lymphocytes.Lymphoproliferations of LGLs range from activated polyclonal expansions to clinically overt leukemias
Flow-cytometric analysis was Clinical and hematological features are heterogeneous in CD8 þ /TCRab þ T-cell LGL (T-LGL) leukemia
Molecular analysis of the T-cell receptor (TCR) repertoire can be a powerful tool in the study of T-cell responses to pathogens and in autoimmune diseases

Summary

Introduction

Lymphoproliferations of LGLs range from activated polyclonal expansions to clinically overt leukemias. T-cell LGL (T-LGL) leukemia is the most common subtype, representing B85% of all LGL leukemia cases diagnosed in western countries. 3–7 There is a frequent association with a wide variety of autoimmune diseases (33%) and other malignancies (13%).[8] Its diagnosis is based on a persistent (46 months) morphologically and/or immunophenotypically increased clonal CD3 þ /CD57 þ LGL population in PB, usually 42 Â 109/l, though a lower count (range 0.4–2 Â 109/l) may be compatible with a diagnosis of T-LGL leukemia.[9,10] T-LGL leukemias can be divided into three groups on the basis of their immunophenotypical and molecular characteristics: CD8 þ , CD4 þ and T-cell receptor (TCR)gd þ T-LGL. It presents in elderly individuals (mean age 60 years) and generally has an indolent clinical course.[3,12] cases with a more aggressive clinical course that are associated with a CD3 þ /CD8 þ /CD56 þ /CD57 À phenotype have been reported as well.[13,14] CD3 þ /CD4 þ /TCRab þ T-LGL leukemia and CD3 þ / TCRgd þ T-LGL leukemia are far less common (o5 and 5–10%, respectively), but a considerable number of cases from both disease entities have recently been described in detail.[15,16]

Methods

Results

Conclusion