High Frequencies of Virus-Specific CD8 + T-Cell Precursors

Abstract

A productive CD8 + T-cell response to a viral infection requires rapid division and proliferation of virus-specific CD8 + T cells. Tetramer-based enrichment assays have recently given estimates of the numbers of peptide-major histocompatibility complex-specific CD8 + T cells in naïve mice, but precursor frequencies for entire viruses have been examined only by using in vitro limiting-dilution assays (LDAs). To examine CD8 + T-cell precursor frequencies for whole viruses, we developed an in vivo LDA and found frequencies of naïve CD8 + T-cell precursors of 1 in 1,444 for vaccinia virus (VV) (∼13,850 VV-specific CD8 + T cells per mouse) and 1 in 2,958 for lymphocytic choriomeningitis virus (LCMV) (∼6,761 LCMV-specific CD8 + T cells per mouse) in C57BL/6J mice. In mice immune to VV, the number of VV-specific precursors, not surprisingly, dramatically increased to 1 in 13 (∼1,538,462 VV-specific CD8 + T cells per mouse), consistent with estimates of VV-specific memory T cells. In contrast, precursor numbers for LCMV did not increase in VV-immune mice (1 in 4,562, with ∼4,384 LCMV-specific CD8 + T cells per VV-immune mouse). Using H-2D b -restricted LCMV GP33-specific P14-transgenic T cells, we found that, after donor T-cell take was accounted for, approximately every T cell transferred underwent a full proliferative expansion in response to LCMV infection. This high efficiency was also seen with memory populations, suggesting that most antigen-specific T cells will proliferate extensively at a limiting dilution in response to infections. These results show that frequencies of naïve and memory CD8 + T cell precursors for whole viruses can be remarkably high.