%0 Journal Article
%A McClanahan, Fabienne
%A Riches, John C
%A Miller, Shaun
%A Day, William P
%A Kotsiou, Eleni
%A Neuberg, Donna
%A Croce, Carlo M
%A Capasso, Melania
%A Gribben, John G
%T Mechanisms of PD-L1/PD-1-mediated CD8 T-cell dysfunction in the context of aging-related immune defects in the Eµ-TCL1 CLL mouse model.
%J Blood
%V 126
%N 2
%@ 0006-4971
%C Washington, DC
%I American Society of Hematology
%M DZNE-2023-00629
%P 212 - 221
%D 2015
%X T-cell defects, immune suppression, and poor antitumor immune responses are hallmarks of chronic lymphocytic leukemia (CLL), and PD-1/PD-L1 inhibitory signaling has emerged as a major immunosuppressive mechanism. However, the effect of different microenvironments and the confounding influence of aging are poorly understood. The current study uses the Eμ-TCL1 mouse model, which replicates human T-cell defects, as a preclinical platform to longitudinally examine patterns of T-cell dysfunction alongside developing CLL and in different microenvironments, with a focus on PD-1/PD-L1 interactions. The development of CLL was significantly associated with changes in T-cell phenotype across all organs and function. Although partly mirrored in aging wild-type mice, CLL-specific T-cell changes were identified. Murine CLL cells highly expressed PD-L1 and PD-L2 in all organs, with high PD-L1 expression in the spleen. CD3(+)CD8(+) T cells from leukemic and aging healthy mice highly expressed PD-1, identifying aging as a confounder, but adoptive transfer experiments demonstrated CLL-specific PD-1 induction. Direct comparisons of PD-1 expression and function between aging CLL mice and controls identified PD-1(+) T cells in CLL as a heterogeneous population with variable effector function. This is highly relevant for therapeutic targeting of CD8(+) T cells, showing the potential of reprogramming and selective subset expansion to restore antitumor immunity.
%K Aging: genetics
%K Aging: immunology
%K Animals
%K B7-H1 Antigen: physiology
%K CD8-Positive T-Lymphocytes: immunology
%K Cell Differentiation: genetics
%K Cell Differentiation: immunology
%K Cells, Cultured
%K Disease Models, Animal
%K Immunoglobulin mu-Chains: genetics
%K Leukemia, Lymphocytic, Chronic, B-Cell: genetics
%K Leukemia, Lymphocytic, Chronic, B-Cell: immunology
%K Leukemia, Lymphocytic, Chronic, B-Cell: pathology
%K Mice
%K Mice, Transgenic
%K Programmed Cell Death 1 Receptor: physiology
%K Proto-Oncogene Proteins: genetics
%K Signal Transduction: immunology
%K B7-H1 Antigen (NLM Chemicals)
%K Cd274 protein, mouse (NLM Chemicals)
%K Immunoglobulin mu-Chains (NLM Chemicals)
%K Pdcd1 protein, mouse (NLM Chemicals)
%K Programmed Cell Death 1 Receptor (NLM Chemicals)
%K Proto-Oncogene Proteins (NLM Chemicals)
%K Tcl1 protein, mouse (NLM Chemicals)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:25979947
%2 pmc:PMC4497962
%R 10.1182/blood-2015-02-626754
%U https://pub.dzne.de/record/258656