title: Abnormal T-cell function in B-cell chronic lymphocytic leukaemia.
abstract: There is increasing evidence of T cell dysfunction in B cell chronic lymphocytic leukaemia (B-CLL) which may contribute to the aetiology and progress of the disease. An absolute CD8+ lymphocytosis correlates with disease progression and low expression of CD4 and CD8 (as found in autoimmune disease) is seen with abnormal expression of other surface molecules. Although the expression of T cell surface activation markers, CD25 and CD152, may be increased on culture in B-CLL serum, response to the common mitogens, PHA and PWM, is reduced. This and the excess of CD8 cells may explain partly the variable cooperation of T cells with B cell production of immunoglobulin in B-CLL. In the context of T cell cross-talk with antigen presenting cells, B-CLL B cells are poor antigen presenters. But the T cells themselves have significant abnormalities of expression of the many antigens and ligands necessary for this process. In particular, they exhibit variable expression of the low affinity and non-specific adhesion molecules LFA-1 and ICAM-1, variable, clonally restricted and skewed expression of the TCR repertoire (implying repeated antigenic stimulation possibly by CLL antigens), reduced CD28 and CD152 expression (implying impairment of ability to start or stop an immune response) and reduced IL2 and CD25 (IL2 R) expression (critical for positive feed-back in maintenance and expansion of the T cell response to antigen presentation). Although the production of IL2 and other cytokines by the T cell in B-CLL may be impaired, production of the anti-apoptotic cytokine IL4 is not and there may be a unique and expanded subset of CD8/CD30 cells capable of releasing IL4. The relationship of this T cell subset to the malignant B cell in vivo is unknown. However, T cells which are CD4+/CD152+/CCR4+ migrate selectively in vitro in response to the chemokine CCL22 (specific for the receptor CCR4) produced by the malignant B cells and are always seen amongst the malignant cells in bone marrow and lymph nodes from B-CLL patients. Other abnormalities of cytokine secretion are described. These findings suggest that the T cell in B-CLL may be unable to start, maintain and complete an immune response to the malignant B cell and other antigens and may be involved directly in sustaining the tumour. However, autologous tumour specific cytotoxicity has been shown in vitro and T cells which recognise tumour-derived heavy chain fragments circulate in vivo. If adoptive immunotherapy of any nature is to succeed in B-CLL, manipulation to optimise these CTL responses is needed to overcome the profound and variable T cell dysfunction in this disease.
authors.affiliation: Plymouth Post-graduate Medical School, Derriford Combined Laboratories, Derriford Hospital, Plymouth PL6 8DH, UK.
authors.forename: S
authors.initials: S
authors.lastname: Scrivener
authors.forename: R V
authors.initials: RV
authors.lastname: Goddard
authors.forename: E R
authors.initials: ER
authors.lastname: Kaminski
authors.forename: A G
authors.initials: AG
authors.lastname: Prentice
mesh_terms: D000917:Antibody Formation; D015703:Antigens, CD / Q000502:physiology; D000951:Antigens, Neoplasm / Q000276:immunology; D000954:Antigens, Surface / Q000502:physiology; D015815:Cell Adhesion Molecules / Q000502:physiology; D003114:Colony-Forming Units Assay; D016207:Cytokines / Q000378:metabolism; D003602:Cytotoxicity, Immunologic; D018450:Disease Progression; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000209:etiology / Q000276:immunology; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000150:complications / Q000276:immunology*; D008213:Lymphocyte Activation / Q000187:drug effects; D008211:Lymphocyte Cooperation; D018655:Lymphocyte Count; D008934:Mitogens / Q000494:pharmacology; D009363:Neoplasm Proteins / Q000276:immunology / Q000502:physiology; D017260:Receptor-CD3 Complex, Antigen, T-Cell / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D000951:Antigens, Neoplasm; D000954:Antigens, Surface; D015815:Cell Adhesion Molecules; D016207:Cytokines; D008934:Mitogens; D009363:Neoplasm Proteins; D017260:Receptor-CD3 Complex, Antigen, T-Cell