Natural specific T cell immunity in patients with B-cell chronic lymphocytic leukaemia (B-CLL) : a clinical and immunological study

Abstract

Analysis of TCRBV (T-cell receptor B variable) gene usage of the T cell repertoire in patients with B cell chronic lymphocytic leukaemia (B-CLL) and age-matched healthy control donors showed that major perturbations were more frequently seen in the CD4+ T cell subset than in CD8 population. Analysis of the CDR3 length polymorphism revealed a significantly higher degree of clonality within the CD4+ and CD8+ T cell repertoire of patients as compared to the normal control population. These results suggest that non-malignant CD4+ T cells as well as CD8+ T cells may be involved in the pathogenesis of B-CLL.

CLL patients showed the presence of a naturally occurring CD4 and CD8 T cell specifically recognizing the leukaemic B cells. Analyses of cytokines by realtime RT-PCR revealed that Thl cytokines were the most frequently observed cytokines expressed by T cells recognizing the autologous tumor B cells. Upregulation of CD80 on the leukaemic B cells was necessary for induction of the specific T cell response. The T cell response was either MHC class I- or class II-restricted.

Analyses of TCR BV gene usage of tumor-restricted T cells showed overexpression 'of certain BVs in CD4 and CD8 T cells as compared to native T cells. Furthermore, analysis of the CDR3 length polymorphism showed that over-expressed BVs shifted from mostly a polyclonal pattern to an oligoclonal/monoclonal pattern after stimulation of T cells with the autologous tumor B cells.

Dendritic cells (DC) were generated in vitro from blood CD14+ cells. Most of the DC exhibited a mature phenotype indicated by CD83 and MHC class II expression, as well as by morphology. CLL DC had a similar expression of accessory molecules as control DC. However the pattern of cytokines was different in CLL as compared to control DC. DC of CLL patients had a similar capacity to present antigen as control DC.

A VH-CDR3 specific T cell response was demonstrated in CLL patients both by proliferation assay and by IFN-gamma production. The T cell specific response could be inhibited by monoclonal antibodies against MHC class Il or MHC class I molecules.

In summary, in B-CLL patients a natural specific T cell response can be demonstrated. However, the biological significance of such a tumor specific immunity remains to be established. The occurrence of leukaemia specific T cells suggests that CLL might a candidate for developing a therapeutic vaccine approach.