T cells from CLL patients exhibit features of T-cell exhaustion but retain capacity for cytokine production

• Published in: Blood 2013-02, Vol.121 (9), p.1612-1621
• Main Authors: Riches, John C., Davies, Jeffrey K., McClanahan, Fabienne, Fatah, Rewas, Iqbal, Sameena, Agrawal, Samir, Ramsay, Alan G., Gribben, John G.
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Antigens, CD - metabolism; Case-Control Studies; CD3 Complex - metabolism; CD8-Positive T-Lymphocytes - metabolism; CD8-Positive T-Lymphocytes - pathology; Cells, Cultured; Cytokines - metabolism; Cytomegalovirus; GPI-Linked Proteins - metabolism; Humans; Leukemia, Lymphocytic, Chronic, B-Cell - immunology; Leukemia, Lymphocytic, Chronic, B-Cell - metabolism; Leukemia, Lymphocytic, Chronic, B-Cell - pathology; Lymphoid Neoplasia; Middle Aged; Programmed Cell Death 1 Receptor - metabolism; Receptors, Immunologic - metabolism; Signaling Lymphocytic Activation Molecule Family; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; T-Lymphocytes - pathology; T-Lymphocytes - physiology
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood-2012-09-457531

T-cell exhaustion, originally described in chronic viral infections, was recently reported in solid and hematologic cancers. It is not defined whether exhaustion contributes to T-cell dysfunction observed in chronic lymphocytic leukemia (CLL). We investigated the phenotype and function of T cells from CLL patients and age-matched controls. CD8+ and CD4+ T cells from CLL patients had increased expression of exhaustion markers CD244, CD160, and PD1, with expansion of a PD1+BLIMP1HI subset. These molecules were most highly expressed in the expanded population of effector T cells in CLL. CLL CD8+ T cells showed functional defects in proliferation and cytotoxicity, with the cytolytic defect caused by impaired granzyme packaging into vesicles and nonpolarized degranulation. In contrast to virally induced exhaustion, CLL T cells showed increased production of interferon-γ and TNFα and increased expression of TBET, and normal IL2 production. These defects were not restricted to expanded populations of cytomegalovirus (CMV)–specific cells, although CMV seropositivity modulated the distribution of lymphocyte subsets, the functional defects were present irrespective of CMV serostatus. Therefore, although CLL CD8+ T cells exhibit features of T-cell exhaustion, they retain the ability to produce cytokines. These findings also exclude CMV as the sole cause of T-cell defects in CLL. •T cells from patients with CLL exhibit features of T-cell exhaustion.•These findings exclude CMV as the sole cause of T-cell defects in CLL.