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Blood, 15 January 2006, Vol. 107, No. 2, pp. 602-609.
Prepublished online as a Blood First Edition Paper on September 8, 2005; DOI 10.1182/blood-2005-06-2234.


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IMMUNOBIOLOGY

Skewed T-cell differentiation in patients with indolent non-Hodgkin lymphoma reversed by ex vivo T-cell culture with {gamma}c cytokines

Andrea Anichini, Roberta Mortarini, Luca Romagnoli, Paola Baldassari, Antonello Cabras, Carmelo Carlo-Stella, Alessandro M. Gianni, and Massimo Di Nicola

From the Human Tumor Immunobiology Unit, Department of Experimental Oncology, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy; the "Cristina Gandini" Bone Marrow Transplantation Unit, Department of Medical Oncology, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy; and the Department of Pathology, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy.

The unfavorable clinical evolution in indolent non-Hodgkin lymphomas suggests defective control of neoplastic growth by the immune system. To address this issue, we evaluated phenotype, function, and maturation profile of CD4+ and CD8+ T cells from peripheral-blood, lymph nodes, or bone marrow of patients with B-cell non-Hodgkin lymphoma (NHL) at diagnosis. T cells from these patients frequently showed an activated but apoptosis-prone phenotype with low frequency of tumor-reactive T cells showing a TH2/Tc2 functional profile in the response to autologous tumor. In peripheral blood or in lymph nodes and bone marrow, and, in comparison to healthy donors, patients' T cells showed a skewed differentiation toward Tnaive and Tcentral memory stages, with low expression of granzyme B and perforin. T-cell culture with autologous tumor in the presence of IL-2, IL-15, and autologous bone marrow–derived cells led to massive T-cell expansion and to differentiation of cytotoxic factor+ CD8+ T cells releasing IFN-{gamma} and killing autologous B-cell tumor in an HLA-class I–restricted fashion. These results suggest impaired T-cell differentiation to effector stage in patients with B-cell NHL, but indicate that T-cell responsiveness to {gamma}c cytokines is retained, thus allowing to promote generation of antitumor T cells for immune intervention.


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