CD3+ T-cell lymphogranular leukemia (TLGL) is classified as a lymphoid neoplasm where the malignant population consists of mature CD3+ T cells that persist in the peripheral circulation over long periods of time.1,2 TLGL mainly affects elderly individuals and presents generally with a slow progression. Individuals with circulating TLGL populations often have rather modest lymphocytosis and are not necessarily symptomatic.3 TLGL populations are monoclonal or, less frequently, biclonal. Their common phenotype is CD3+CD8+CD45RA+CD27-(CD57+/-), which is virtually indistinguishable from that of normal effector CD8+ T cells.2,4 Because of these observations, it has been argued whether TLGL clonopathy is truly neoplastic or represents instead the epiphenomenon of an immunoregulatory disorder. In the December 2002 issue of Blood, V. Bigouret and colleagues5 propose that TLGL cells may correspond to CD8+ effector T-cell populations arising as an extreme form of immune response to chronic pathologies. These pathologies, however, along with the antigen specificity of TLGL cells, remain thus far unknown. We have recently described, in melanoma patients, a CD3+CD8+CD45RA+ subset of T cells exerting ex vivo tumor-specific effector functions, including interferon γ IFN-γ secretion and cytolytic activity.6 In an HLA-A2–expressing patient, these cells accounted for about 5% of the circulating CD8+ T lymphocytes and were composed of a monoclonal population specific for a single antigenic determinant from tyrosinase, a self-antigen expressed by malignant melanoma tumor cells and cells of the melanocytic lineage, but not by other normal cells. This cell population persisted at a stable level over 3 years, including more than one year after the resection of a single metastatic lesion that left the patient free of detectable disease to date. As assessed by using HLA-A2/peptide multimers incorporating peptide tyrosinase 368-376 in addition to CD3, CD8, and CD45RA, these cells expressed CD57, CD69, perforin, and granzyme B, but were CD45RO-, CD27-, CD28-, CLA-, and HLA-DR-.6 In addition, they expressed several natural killer (NK) receptors including CD94 (but not the inhibitory form associated with NKG2A), p58.2, and ILT2 (D.V., unpublished data, May 2002). Thus, both the prevalence and the phenotype of this population of cells found in a patient with melanoma were undistinguishable from those of TLGL cells. Our data provide strong support to the hypothesis of V. Bigouret and colleagues. Although the frequency of TLGL populations in cancer patients remains to be assessed, it is likely that these populations also include T cells arising as immune responses to chronic diseases, including those caused by pathogens. It has been suggested that in TLGL patients the appearance of clinical symptoms (neutropenia and/or autoimmune phenomena) may occur as a consequence of exposure to antigen.5,7 This raises questions about the opportunity and the possible outcome of antigen-specific active immunotherapy in these cancer patients. The molecular mechanisms that control the expansion and persistence of single antigen-specific CD8+ effector T-cell populations exhibiting characteristics at the edge between normality and pathology remain unknown. Their elucidation may provide information relevant to the development of novel strategies for both the controlled use of CD8+ T cells in immunotherapy and for the treatment of TLGL-related pathologies.