Loss of T-lymphocyte clonal dominance in patients with myelodysplastic syndrome responsive to immunosuppression

Abstract

Evidence suggests that T lymphocyte-mediated inhibition of hematopoiesis in myelodysplastic syndrome (MDS) contributes to cytopenia in some patients and can be reversed by treatment with immunosuppression. We examined the T-cell repertoires of 12 patients with MDS before and after antithymocyte globulin (ATG)-based treatment by T-cell receptor Vbeta (TCR-Vbeta) spectratype analysis. The average number of TCR-Vbeta families with skewed spectratypes, representative of clonal or oligoclonal T-cell populations, was 7.6 in MDS patients before treatment and 3.2 in healthy controls (P =.02). Four patients who recovered effective hematopoiesis after treatment lost prominent, skewed peaks on their spectratypes, suggesting loss or diminution of overrepresented clonal T-cell populations. In contrast, patients who did not recover effective hematopoiesis showed persistently skewed repertoires 3 to 6 months after treatment. In 3 patients with skewed repertoires, cDNA from the complementarity-determining region 3 (CDR3) of 4 TCR-Vbeta families was cloned and repetitively sequenced, confirming clonal T-cell dominance in each family. In one nonresponder, 16 of 19 CDR3 sequences were identical, demonstrating that 9.3% of the total T-cell population was made up of a single clone. By 6 months after treatment, this clone persisted on both spectratype and DNA sequence complementarity and when analyzed by flow cytometry was shown to be CD8(+)/CD45RA(+)/HLA-DR(-). T-cell clones were not anergic because they could be expanded 4-fold in vitro. Our results demonstrate that predominant clonal T cells that appear to be antigen-driven persist in patients with MDS unresponsive to immunosuppression, but predominant clones regress in responders to immunosuppression.