Abstract
Chronic lymphocytic leukemia develops within a complex network driven by genetic mutations and microenvironmental interactions. Among the latter a complex interplay with the immune system is established by the clone. Next to a proposed recruitment of support from T and myeloid cells, potential anti-CLL immune reactions need to be subverted.By using TCL1 mice as a CLL model, we show that TCR-Vβ7+ NK1.1+ T cells are overrepresented in this disease model and constitute a main subset of peripheral CD3+ cells with biased TCR usage, showing that these cells account for a major part for T cell skewing in TCL1 mice. Moreover, we show that overrepresentation is dependent on CD1d expression in TCL1 mice, implicating that these cells belong to a NKT-like cell fraction which are restricted to antigen presented by the MHC-like surface marker CD1d. Accordingly, we observed a high fraction of CD161+ cells within overrepresented T cells in CLL patients and we found downregulation of CD1d on the surface of CLL cells, both in TCL1 mice and patients. Finally, we show that in TCL1 mice, CD1d deficiency resulted in shortened overall survival. Our results point to an interaction between CLL and CD161+ T cells that may represent a novel therapeutic target for immune modulation.
Highlights
While immunotherapy has been under evaluation for many decades, only recent advances in effectively modulating the patient’s immune system have made immunotherapy a promising and appealing strategy in cancer treatment
By using TCL1 mice as a chronic lymphocytic leukemia (CLL) model, we show that TCR-Vβ7+ NK1.1+ T cells are overrepresented in this disease model and constitute a main subset of peripheral CD3+ cells with biased TCR usage, showing that these cells account for a major part for T cell skewing in TCL1 mice
Immune interactions with cognate T cells are suggested to play a significant role in disease pathogenesis, since it was observed that in CLL, the T cell compartment exhibits a range of dysfunctions together with the frequent occurrence of overrepresented Vβ-specific T cells, which are often oligo- or monoclonal [5, 17, 18, 23,24,25,26]
Summary
While immunotherapy has been under evaluation for many decades, only recent advances in effectively modulating the patient’s immune system have made immunotherapy a promising and appealing strategy in cancer treatment. With its intricate dysregulation of the T cell system, chronic lymphocytic leukemia (CLL) may be an especially interesting target disease for immunotherapeutic approaches [1]. CD1d restricted T cells comprise a T cell subset which is activated by lipid antigen presented by the monomorphic MHC class I like surface molecule CD1d. These cells are grouped as natural killer (NK) T cells which constitute a subset of innate T cells which share features of both innate and adaptive immunity [8,9]
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