Control of chronic lymphocytic leukemia development by clonally-expanded CD8+ T-cells that undergo functional exhaustion in secondary lymphoid tissues

Leukemia. 2019 Mar;33(3):625-637. doi: 10.1038/s41375-018-0250-6. Epub 2018 Sep 28.

Abstract

Chronic lymphocytic leukemia (CLL) is associated with substantial alterations in T-cell composition and function. However, the role of T-cells in CLL remains largely controversial. Here, we utilized the Eµ-TCL1 mouse model of CLL as well as blood and lymph node samples of CLL patients to investigate the existence of anti-tumoral immune responses in CLL, and to characterize involved immune cell populations. Thereby, we identified an oligoclonal CD8+ effector T-cell population that expands along with CLL progression and controls disease development. We further show that a higher percentage of CD8+ effector T-cells produces IFNγ, and demonstrate that neutralization of IFNγ results in faster CLL progression in mice. Phenotypical and functional analyses of expanded CD8+ effector T-cells show significant differences in disease-affected tissues in mice, with cells in secondary lymphoid organs harboring hallmarks of activation-induced T-cell exhaustion. Notably, we further describe a respective population of exhausted CD8+ T-cells that specifically accumulate in lymph nodes, but not in peripheral blood of CLL patients. Collectively, these data emphasize the non-redundant role of CD8+ T-cells in suppressing CLL progression and highlight their dysfunction that can be exploited as target of immunotherapy in this malignancy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD8-Positive T-Lymphocytes / metabolism
  • CD8-Positive T-Lymphocytes / pathology*
  • Humans
  • Immunotherapy / methods
  • Interferon-gamma / metabolism
  • Leukemia, Lymphocytic, Chronic, B-Cell / metabolism
  • Leukemia, Lymphocytic, Chronic, B-Cell / pathology*
  • Lymph Nodes / pathology
  • Lymphocyte Activation / physiology
  • Lymphoid Tissue / metabolism
  • Lymphoid Tissue / pathology*
  • Mice
  • Mice, Inbred C57BL

Substances

  • Interferon-gamma