Dysregulated signaling, proliferation and apoptosis impact on the pathogenesis of TCRγδ+ T cell large granular lymphocyte leukemia

Abstract

TCRγδ+ T-LGL leukemia is a rare form of chronic mature T cell disorders in elderly, which is generally characterized by a persistently enlarged CD3+CD57+TCRγδ+ large granular lymphocyte population in the peripheral blood with a monoclonal phenotype. Clinically, the disease is heterogeneous, most patients being largely asymptomatic, although neutropenia, fatigue and B symptoms and underlying diseases such as autoimmune diseases or malignancies are also often observed. The etiology of TCRγδ+ T-LGL proliferations is largely unknown. Here, we aimed to investigate underlying molecular mechanisms of these rare proliferations by performing gene expression profiling of TCRγδ+ T-LGL versus normal TCRγδ+ T cell subsets. From our initial microarray dataset we observed that TCRγδ+ T-LGL leukemia forms a separate group when compared with different healthy control TCRγδ+ T cell subsets, correlating best with the healthy TemRA subset. The lowest correlation was seen with the naive subset. Based on specific comparison between healthy control cells and TCRγδ+ T-LGL leukemia cells we observed up-regulation of survival, proliferation and hematopoietic system related genes, with a remarkable down-regulation of apoptotic pathway genes. RQ-PCR validation of important genes representative for the dataset, including apoptosis (XIAP, CASP1, BCLAF1 and CFLAR), proliferation/development (ID3) and inflammation (CD28, CCR7, CX3CR1 and IFNG) processes largely confirmed the dysregulation in proliferation and apoptosis. Based on these expression data we conclude that TCRγδ+ T-LGL leukemia is likely the result of an underlying aberrant molecular mechanisms leading to increased proliferation and reduced apoptosis.

Next-Generation Sequencing Analysis of the Human TCRγδ+ T-Cell Repertoire Reveals Shifts in Vγ- and Vδ-Usage in Memory Populations upon Aging

“…The TCRγδ+ T-LGL leukemia-related receptor from case 10 to 200 was found twice in older individuals (naive subset, 56-year-old male; effector subset, 70-year-old male) (Table 1 ). Although the numbers are low, the fact that two TCRγδ+ T-LGL leukemia-related receptors could specifically be identified in effector cells of elderly would support the idea that TCRγδ+ T-LGL leukemia cells originate from the normal TCRγδ repertoire, especially from antigen-experienced TCRγδ+ T-cells of individuals of older age ( 13 , 48 , 49 ).…”

“…This was in clear contrast to circulating mature TCRγδ+ T-cells that showed Vγ9/Vδ2 receptor skewing with high inter-sample variation and donor-specific patterns. As we recently showed significant effects of aging on maturation profiles of TCRγδ+ T-cells ( 49 ), we investigated the immune repertoire composition of different TCRγδ+ T-cell subsets including naive, central, and effector memory, and effector cells. Even though the naive TCRγδ+ T-cell population shrinks upon aging ( 3 , 5 , 49 ), its diversity—being the primary source for mounting immune responses—was maintained in elderly individuals.…”

“…As we recently showed significant effects of aging on maturation profiles of TCRγδ+ T-cells ( 49 ), we investigated the immune repertoire composition of different TCRγδ+ T-cell subsets including naive, central, and effector memory, and effector cells. Even though the naive TCRγδ+ T-cell population shrinks upon aging ( 3 , 5 , 49 ), its diversity—being the primary source for mounting immune responses—was maintained in elderly individuals. To date, only one study documented the maintenance of the naive CD4+ TCRαβ+ T-cell repertoire until the age of 70, after which the repertoire profoundly declined ( 51 ) [reviewed in Ref.…”

“…Also, CMV is known to elicit Vδ1+ TCRγδ+ T-cell-specific responses ( 17 ). Additionally, we have recently demonstrated the effect of CMV on the TCRγδ+ T-cell immune system, through increasing Vδ1+ TCRγδ+ T-cells in elderly carrying CMV ( 49 ), and it has been shown that latent CMV carriage is related to the expansion of CMV specific T-cells ( 54 ). When zooming in on the antigen-binding part, the CDR3 region, we could indeed identify CMV-specific CDR3 regions in a few donors, albeit without a significant aging effect.…”

Human γδ TCR Repertoires in Health and Disease

“…Upon ageing, Kallemeijn and colleagues reported shrinking of the naïve γδ T cell population (CD45RA + CD27 + CD197 + ), while repertoire diversity was maintained [70,75]. Moreover, a tendency for a decreased Vγ9 usage and an increase of Vγ2-5 and Vγ8 chain usage in elderly individuals was shown for effector (CD45RA -CD45RO + CD27 -CD197 -) and central memory γδ T cells (CD45RA -CD45RO + CD27 + CD197 + ) [70,75], as well as a general reduction of paired Vγ9Vδ2 + TCRs in some individuals [66]. Furthermore, γδ TCR repertoires in healthy elderly individuals are characterized by large clonal expansions of particular non-Vγ9Vδ2 + clonotypes that could reflect the history of antigen challenge [66].…”