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Examination of CD8⁺ T Cell Function in Humans Using MHC Class I Tetramers: Similar Cytotoxicity but Variable Proliferation and Cytokine Production Among Different Clonal CD8⁺ T Cells Specific to a Single Viral Epitope

Dong-Gyun Lim^1,*, Katarzyna Bieganowska Bourcier^1,*, Gordon J. Freeman and David A. Hafler^2,*

^* Laboratory of Molecular Immunology, Center for Neurologic Diseases, Brigham and Women’s Hospital and Harvard Medical School, and Department of Adult Oncology, Dana-Farber Cancer Institute, Boston, MA 02115

Following infection by human T cell lymphotrophic virus-I (HTLV-I), high frequencies of polyclonal Tax11–19-reactive CD8⁺ T cells can be detected in the peripheral blood. To investigate whether there are differences in the effector functions of these cells, we generated a panel of Tax11–19-reactive T cell clones by single cell sorting of HLA-A2/Tax11–19 tetramer binding CD8⁺ T cells followed by repeated stimulation with PHA and IL-2. Examination of the TCRs revealed 17 different T cell clones with unique clonal origins. Nine representative CD8⁺ T cell clones showed a similar cytotoxic dose-response activity against Ag-pulsed target cells, even though they express different TCRs. This cytotoxic effector function was not influenced by the engagement of either CD28 or CD2 costimulatory molecules. In contrast to the cytotoxic activity, qualitatively different degrees of proliferative response and cytokine secretion were observed among T cell clones of different clonal origin. The induction of proliferation and cytokine secretion required the engagement of costimulatory molecules, particularly CD2-LFA-3 interaction. These results indicate that functionally diverse, polyclonal CTL populations can be activated specific to a single immunodominant viral epitope; they can manifest virtually identical cytotoxic effector function but have marked differences in proliferation and cytokine secretion.

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