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Br J Haematol. 2015 Aug;170(4):515-22. doi: 10.1111/bjh.13467. Epub 2015 May 4.

Chronic lymphocytic leukaemia induces an exhausted T cell phenotype in the TCL1 transgenic mouse model.

Author information

1
Laboratory for Immunological and Molecular Cancer Research, 3rd Medical Department with Haematology, Medical Oncology, Haemostaseology, Infectiology and Rheumatology, Oncologic Centre, Paracelsus Medical University, Salzburg, Austria.
2
Salzburg Cancer Research Institute, Salzburg, Austria.

Abstract

Although chronic lymphocytic leukaemia (CLL) is a B cell malignancy, earlier studies have indicated a role of T cells in tumour growth and disease progression. In particular, the functional silencing of antigen-experienced T cells, called T cell exhaustion, has become implicated in immune evasion in CLL. In this study, we tested whether T cell exhaustion is recapitulated in the TCL1(tg) mouse model for CLL. We show that T cells express high levels of the inhibitory exhaustion markers programmed cell death 1 (PDCD1, also termed PD-1) and lymphocyte-activation gene 3 (LAG3), whereas CLL cells express high levels of CD274 (also termed PD-ligand 1). In addition, the fraction of exhausted T cells increases with CLL progression. Finally, we demonstrate that exhausted T cells are reinvigorated towards CLL cytotoxicity by inhibition of PDCD1/CD274 interaction in vivo. These results suggest that T cell exhaustion contributes to CLL pathogenesis and that interference with PDCD1/CD274 signalling holds high potential for therapeutic approaches.

KEYWORDS:

PDCD1; T cell exhaustion; chemoimmunotherapy; chronic lymphocytic leukaemia; tumour surveillance

PMID:
25940792
PMCID:
PMC4687418
DOI:
10.1111/bjh.13467
[Indexed for MEDLINE]
Free PMC Article

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