title: T cells from CLL patients exhibit features of T-cell exhaustion but retain capacity for cytokine production.
abstract: 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.
authors.affiliation: Department of Haemato-Oncology, Barts Cancer Institute, a CR-UK Centre of Excellence, Queen Mary University of London, London, United Kingdom. johnriches@doctors.org.uk
authors.forename: John C
authors.initials: JC
authors.lastname: Riches
authors.forename: Jeffrey K
authors.initials: JK
authors.lastname: Davies
authors.forename: Fabienne
authors.initials: F
authors.lastname: McClanahan
authors.forename: Rewas
authors.initials: R
authors.lastname: Fatah
authors.forename: Sameena
authors.initials: S
authors.lastname: Iqbal
authors.forename: Samir
authors.initials: S
authors.lastname: Agrawal
authors.forename: Alan G
authors.initials: AG
authors.lastname: Ramsay
authors.forename: John G
authors.initials: JG
authors.lastname: Gribben
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015703:Antigens, CD / Q000378:metabolism; D017252:CD3 Complex / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism / Q000473:pathology; D016022:Case-Control Studies; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism*; D058851:GPI-Linked Proteins / Q000378:metabolism; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008875:Middle Aged; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism; D011971:Receptors, Immunologic / Q000378:metabolism; D000071176:Signaling Lymphocytic Activation Molecule Family; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000502:physiology*
chemical_list: D015703:Antigens, CD; C114505:CD160 protein, human; C084093:CD244 protein, human; D017252:CD3 Complex; D016207:Cytokines; D058851:GPI-Linked Proteins; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D011971:Receptors, Immunologic; D000071176:Signaling Lymphocytic Activation Molecule Family