CD8+ T-cell selection, function, and death in the primary immune response in vivo
Margaret F.C. Callan, … , Chris Hatton, Andrew J. McMichael
Margaret F.C. Callan, … , Chris Hatton, Andrew J. McMichael
Published November 15, 2000
Citation Information: J Clin Invest. 2000;106(10):1251-1261. https://doi.org/10.1172/JCI10590.
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Article

CD8+ T-cell selection, function, and death in the primary immune response in vivo

Abstract

The primary immune response to Epstein Barr virus (EBV) is characterized by striking proliferation of EBV-specific CD8+ T cells. In this study we have investigated the clonal composition and functional properties of the cells mediating this primary response and have analyzed the mechanisms that control the downregulation of the primary response and the selection of memory cells. We show that massively expanded T-cell clones often dominate the primary antigen-specific T-cell response. Despite the enormous extent of expansion, the virus-specific T cells express high levels of intracellular perforin and are potently cytotoxic. They are, however, functionally heterogeneous in their ability to secrete proinflammatory cytokines, with subpopulations of the antigen-specific T cells being hyporesponsive. The primary response is closely regulated, and the majority of cells are programmed to die via a cytokine-rescuable pathway, leaving only small populations of memory T cells surviving. Comparison of the clonal composition of primary and memory responses in vivo shows that the clones that dominate the primary response are relatively heavily culled during the downregulation of the primary response and the establishment of T-cell memory.

Authors

Margaret F.C. Callan, Chrysoula Fazou, Hongbing Yang, Tim Rostron, Kathryn Poon, Chris Hatton, Andrew J. McMichael

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Cytotoxicity of EBV-specific T cells during the primary immune response....
Cytotoxicity of EBV-specific T cells during the primary immune response. (a) PBMCs from donor NS30, an HLA-A2+ individual with IM, and donor NS28, an HLA-B8+ individual with IM, were stained with an A2/GLCTLVAML or a B8/RAKFKQLL tetrameric complex and with an anti-CD8 mAb. The frequency (%) of CD8+ T cells that stain with the tetrameric complex is shown. PBMCs from these two patients were used as effector cells in chromium-release assays. PBMCs from donor NS30 caused specific lysis of target cells prepulsed with the GLCTLVAML peptide (b), and PBMCs from donor NS28 caused specific lysis of the targets prepulsed with the RAKFKQLL peptide (c). PBMCs from the HLA-B8+ donor were stained with the B8/RAKFKQLL tetrameric complex, with anti-CD8, and then were fixed, permeabilized, and stained for intracellular perforin expression. Perforin expression on CD8+ T cells was bimodal with 57% of CD8+ T cells being perforin bright. All the HLA-B8/RAKFKQLL tetramer–reactive T cells were perforin bright. The FL-1 threshold was set using a FITC-conjugated IgG2b control mAb.