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Although certain T\u2010cell subsets have been reported to be of prognostic significance in this disease, their interplay is complex and it remains incompletely understood which of these subsets significantly drive CLL progression. Here, we determined immunological profiles of 24 circulating T\u2010cell subsets from 79 untreated individuals by multiparametric flow cytometry. This screening cohort included healthy donors, patients with monoclonal B\u2010cell lymphocytosis (MBL), Rai 0 CLL and advanced CLL. We applied multidimensional scaling analysis as rigorous and unbiased statistical tool to globally assess the composition of the circulating T\u2010cell environment and to generate T\u2010cell scores reflecting its integrity. These scores allowed clear distinction between advanced CLL and healthy controls, whereas both MBL and Rai 0 CLL showed intermediate scores mirroring the biological continuum of CLL and its precursor stages. T\u2010cell stimulation and suppression assays as well as longitudinal T\u2010cell profiling showed an increasingly suppressive regulatory function initiating at the MBL stage. Effector function was impaired only after transition to CLL and partially recovered after chemoimmunotherapy. In an independent validation cohort of 52 untreated CLL cases, aberrant T\u2010cell profiles were significantly associated with shorter time to treatment independently of other prognostic parameters. Random forest modeling predicted regulatory T\u2010cell, gamma\/delta and NKT\u2010cells, as well as exhaustion of the CD8+ subset as potential drivers of progression. Our data illustrate a pathological T\u2010cell environment in MBL that evolves toward a more and more suppressive and prognostically relevant profile across the disease stages.<\/jats:p>","DOI":"10.1002\/ijc.28884","type":"journal-article","created":{"date-parts":[[2014,4,11]],"date-time":"2014-04-11T05:48:04Z","timestamp":1397195284000},"page":"2370-2379","source":"Crossref","is-referenced-by-count":27,"title":["Multidimensional scaling analysis identifies pathological and prognostically relevant profiles of circulating T\u2010cells in chronic lymphocytic leukemia"],"prefix":"10.1002","volume":"135","author":[{"given":"Anne","family":"Rissiek","sequence":"first","affiliation":[{"name":"Institute of Immunology University Medical Center Hamburg\u2010Eppendorf Hamburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Schulze","sequence":"additional","affiliation":[{"name":"Systems Biology Center for Molecular Neurobiology Hamburg (ZMNH), 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