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

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.

Figure 1

Relative frequency (%) of associated cytopenias, autoimmune diseases and malignancies in CD8⁺/TCRαβ⁺, CD4⁺/TCRαβ⁺ and TCRγδ⁺ T-LGL leukemia.

Figure 2

Frequencies of V-J pairing in TCRαβ⁺ T-LGL and TCRγδ⁺ T-LGL leukemia. Highly diverse Vα-Jα (a) and Vβ-Jβ (b) combinations are seen in our cohort of 26 patients with CD8⁺ T-LGL leukemia, while the Vβ-Jβ pairing is clearly non-random in monoclonal CD4⁺ T-LGL proliferations (c). Also in TCRγδ⁺ T-LGL leukemia limited combinatorial diversity of TCRG and TCR genes (d and e, respectively) is seen. (Blue to purple rectangular bands) J genes and (red to cyan rectangular bands) V genes. The width of the bands is proportional to the number of times the V and J genes are connected. This figure was generated using the Circos software package.

Figure 3

Sequence logos of selected subsets in T-LGL leukemia. (a) Subset 1 comprises 13 Vβ13.1-Jβ1.1/ Jβ1.5 gene rearrangements in CD4⁺ T-LGL leukemia cases, characterized by pronounced overall similarity. (b) The largest high-level subset in the present study is present in subset 2, comprising clonally expanded CD4⁺ T-LGL showing Vβ13.1-Jβ1.1. (c) Low level clustering was seen in Vβ8/Vβ13-Jβ1.5 gene rearrangements in two CD4⁺ LGL and two CD8⁺ LGL cases. (d) Some higher level clustering is present in Vβn.-Jβ2.3/2.7 gene rearrangements in four CD8⁺ T-LGL leukemia cases. The height of symbols within the stack indicates the relative frequency of each amino acid at that position. Amino-acid position is according to the IMGT numbering for the V domain. This figure was generated using WebLogo (http://weblogo.berkeley.edu/).