CD8+ T-cell selection, function, and death in the primary immune response in vivo
Margaret F.C. Callan, Chrysoula Fazou, Hongbing Yang, Tim Rostron, Kathryn Poon, Chris Hatton, Andrew J. McMichael
Margaret F.C. Callan, Chrysoula Fazou, Hongbing Yang, Tim Rostron, Kathryn Poon, Chris Hatton, Andrew J. McMichael
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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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Cytokine secretion by EBV-specific T cells during the primary immune res...
Cytokine secretion by EBV-specific T cells during the primary immune response. PBMCs from HLA-A2+ individuals with IM (NS120 and NS122) were stained with the HLA-A2/GLCTLVAML tetrameric complex. PBMCs from NS120 were then cultured in vitro for 6 hours in the absence (a and b) or the presence (c and d) of 10 μM GLCTLVAML peptide in R10 supplemented with rIL-2. PBMCs from NS122 were cultured in vitro for 6 hours in the absence (e and f) or presence (g and h) of an autologous lymphoblastoid B-cell line (at a ratio of 1 B cell/1 PBMC) prepulsed with 10 μM GLCTLVAML peptide in R10 supplemented with rIL-2. Brefeldin A was added to the cultures after the first hour. Cells were surface-stained with an anti-CD8 mAb, fixed, permeabilized, and stained for intracellular IFN-γ (a, c, e, and g) or MIP1 β (b, d, f, and h). Only CD8+ T cells were included in the analyses. The frequency (%) of tetramer-reactive T cells that stained positively with mAb’s specific for IFN-γ or MIP1 β is shown.