Expanded CD8+ T cells of murine and human CLL are driven into a senescent KLRG1+ effector memory phenotype
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Altered numbers and functions of T cells have previously been demonstrated in chronic lymphocytic leukemia (CLL) patients. However, dynamics and specific T-cell subset alterations have not been studied in great detail. Therefore, we studied CLL blood lymphocyte subsets of individual patients in a longitudinal manner. Dynamic expansions of blood CD4 + and CD8 + T-cell numbers were consistently associated with a progressively increasing CLL leukemic compartment. Interestingly, the T-cell subset expansion over time was more pronounced in CD38 + CLL. Additionally, we performed gene expression profiling of CD3 + T cells of CLL patients and normal donors. Using gene set enrichment analysis, we found significant enrichment of genes with higher expression in CLL T cells within CD8+ effector memory and terminal effector T-cell gene signatures. In agreement with these data, we observed a marked expansion of phenotypic CD8 + effector memory T cells in CLL by flow cytometry. Moreover, we observed that increments of CD8 + effector memory T cells in human CLL and also mouse CLL (Eμ-TCL1 model) were due to an expansion of the inhibitory killer cell lectin-like receptor G1 (KLRG1) expressing cellular subset. Furthermore, higher plasma levels of the natural KLRG1 ligand E-cadherin were detected in CLL patients compared to normal donor controls. The predominance of KLRG1+ expression within CD8+ T cells in conjunction with increased systemic soluble E-cadherin might significantly contribute to CLL immune dysfunction and might additionally represent an important component of the CLL microenvironment.
KeywordsChronic lymphocytic leukemia Gene set enrichment analysis CD8+ T cells KLRG1
We thank Ute Schmücker and Anja Führer for excellent technical assistance and Brigitte Fischer for help with compiling patient data. We are grateful to Carlo M. Croce for his permission to use Eμ-TCL1 transgenic mice. We thank Günter Fingerle-Rawson for providing Eμ-TCL1 transgenic mice. We are grateful to Peter Horn, Marc Seifert and Ralf Küppers for assistance organizing normal donor blood samples. This work was supported by a grant to J.D. from the Ministerium für Schule, Wissenschaft und Forschung des Landes Nordrhein-Westfalen. J.R.G. receives grant support by the Kompetenznetzwerk Stammzellforschung Nordrhein-Westfalen.
Conflict of interest
The authors declare no competing financial interest.
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