The limits of protection by "memory" T cells in Ig-/- mice persistently infected with a gamma-herpesvirus

Abstract

Can CD4(+) and CD8(+) "memory" T cells that are generated and maintained in the context of low-level virus persistence protect, in the absence of antibody, against a repeat challenge with the same pathogen? Although immune T cells exert effective, long-term control of a persistent gamma-herpesvirus (gammaHV68) in Ig(-/-) microMT mice, subsequent exposure to a high dose of the same virus leads to further low-level replication in the lung. This lytic phase in the respiratory tract is dealt with effectively by the recall of memory T cells induced by a gammaHV68 recombinant (M3LacZ) that does not express the viral M3 chemokine binding protein. At least for the CD8(+) response, greater numbers of memory T cells confer enhanced protection in the M3LacZ-immune mice. However, neither WT gammaHV68 nor the minimally persistent M3LacZ primes the T cell response to the extent that a WT gammaHV68 challenge fails to establish latency in the microMT mice. Memory CD4(+) and CD8(+) T cells thus act together to limit gammaHV68 infection but are unable to provide absolute protection against a high-dose, homologous challenge.

Fig. 1.

Replication of the γHVW and BAC–GFP viruses in the lungs of female Ig^–/– μMT mice. The 10- to 12-week-old mice were infected i.n. with 10⁶ PFU of γHVW or BAC–GFP, then lungs were collected from three individuals (per group) on d3, d5, and d7, homogenized, and assayed for plaque formation on 3T12 cells. The plaques were fixed and stained with Giemsa (γHVW) or counted under a fluorescence microscope (BAC–GFP). Virus titers are expressed as log₁₀ PFU/ml. The asterisk designates values that are significantly different (P ≤ 0.05).

Fig. 2.

The virus-specific CD8⁺ T cell response in μMT mice that were previously uninfected (naïve) or primed i.p. (2 × 10⁴ PFU) with γHVCam or M3LacZ before i.n. challenge on d145 with a 1:1 mixture of γHVW and BAC–GFP (2 × 10⁶ PFU). (A–C) The number of CD8⁺D^bp56⁺ T cell calculated from the percentage of cells staining and the total cell counts (data not shown). (D–F) The values for the CD8⁺K^bp79⁺ set. The results are expressed as mean ± SD. The asterisk designates differences that were significant at P ≤ 0.05.