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Chemokine C Receptor 7 Expression and Protection of Circulating CD8⁺ T Lymphocytes from Apoptosis

Authors' Affiliations: Departments of ¹ Pathology and ² Otolaryngology, University of Pittsburgh School of Medicine and ³ University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania

Requests for reprints: Theresa L. Whiteside, University of Pittsburgh Cancer Institute, Research Pavilion at the Hillman Cancer Center, 5117 Centre Avenue, Suite 1.27, Pittsburgh, PA 15213-1863. Phone: 412-624-0096; Fax: 412-624-0264; E-mail: whitesidetl{at}upmc.edu.

Chemokine C receptor 7 (CCR7) expression is important for lymphocyte homing to tissues. We hypothesized that CCR7 also plays a role in CD8⁺ T-cell protection from apoptosis. Its expression was determined on circulating T cells in patients with cancer and related to that of molecules responsible for lymphocyte susceptibility/resistance to apoptosis. Peripheral blood mononuclear cells were obtained from 36 patients with squamous cell carcinoma of the head and neck and 16 normal controls. Multicolor flow cytometry was used to evaluate CCR7, Fas, Bax, and Bcl-2 expression in CD8⁺ T cells. Annexin V binding to CD8⁺CCR7⁺ and CD8⁺CCR7^– T-cell subsets was compared. Fewer CD8⁺CCR7⁺ T cells bound Annexin V than CD8⁺CCR7^– T cells in normal control and patients (P < 0.0001). CCR7 expression correlated with higher Bcl-2 but lower Bax and Fas expression levels in CD8⁺ T cells in both normal control and patients (P < 0.0001). In patients, the CD8⁺CCR7⁺ subset was reduced relative to normal control (P = 0.008) and replaced with an excess of apoptosis-sensitive CD8⁺CCR7^– T cells. To study CCR7 signaling, CD8⁺ T cells were stimulated with CCR7 ligands, chemokine C ligands 19 or 21. Ligand binding to CCR7 resulted in phosphorylation of Akt and increased Bcl-2 expression in CD8⁺CCR7⁺ T cells, suggesting that CCR7 protects effector T cells from apoptosis through the phosphatidylinositol 3-kinase/Akt pathway. The absence of CCR7 expression on the majority of CD8⁺ T cells in the peripheral circulation of patients with squamous cell carcinoma of the head and neck contributes to apoptosis and a rapid turnover of these effector cells.

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