Compromised influenza virus-specific CD8(+)-T-cell memory in CD4(+)-T-cell-deficient mice - PubMed (original) (raw)

Compromised influenza virus-specific CD8(+)-T-cell memory in CD4(+)-T-cell-deficient mice

Gabrielle T Belz et al. J Virol. 2002 Dec.

Abstract

The primary influenza A virus-specific CD8(+)-T-cell responses measured by tetramer staining of spleen, lymph node, and bronchoalveolar lavage (BAL) lymphocyte populations were similar in magnitude for conventional I-A(b+/+) and CD4(+)-T-cell-deficient I-A(b-/-) mice. Comparable levels of virus-specific cytotoxic-T-lymphocyte activity were detected in the inflammatory exudate recovered by BAL following challenge. However, both the size of the memory T-cell pool and the magnitude of the recall response in the lymphoid tissues (but not the BAL specimens) were significantly diminished in mice lacking the CD4(+) subset. Also, the rate of virus elimination from the infected respiratory tract slowed at low virus loads following challenge of naïve and previously immunized I-A(b-/-) mice. Thus, though the capacity to mediate the CD8(+)-T-cell effector function is broadly preserved in the absence of concurrent CD4(+)-T-cell help, both the maintenance and recall of memory are compromised and the clearance of residual virus is delayed. These findings are consistent with mathematical models that predict virus-host dynamics in this, and other, models of infection.

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Figures

FIG. 1.

FIG. 1.

Lung virus titers following primary (A) or secondary (B) challenge of I-A b+/+ and I-A _b_−/− mice. Naïve (A) or PR8-primed (108.5 EID50 i.p. 6 weeks earlier) (B) mice were given 106.8 EID50 i.n. and sampled at the intervals shown. Log10 dilutions of lung homogenate were used to infect embryonated chicken eggs, and endpoint titrations were determined by a hemagglutination inhibition assay of allantoic fluid. The data are expressed as means ± standard deviations (SD) for groups of five mice each. No virus was recovered from five naïve I-A _b_−/− mice sampled at 19 days after infection with the HKx31 virus strain.

FIG. 2.

FIG. 2.

Peptide-specific CTL activity in the inflammatory cell population recovered by BAL of the infected respiratory tract following secondary i.n. challenge with the HK31 influenza A virus 8 days earlier (see the legend for Fig. 1). The EL4 (H2b) target cells were pulsed with either the NP366 or the PA224 peptide prior to use in a standard 6-h 51Cr release assay. Lytic activities were calculated for the CD8+ DbNP366+ and CD8+ DbPA224+ tetramers as determined by tetramer staining (data not shown).

FIG. 3.

FIG. 3.

Kinetic analysis of the DbNP366 and DbPA224 epitope-specific CD8+-T-cell response in I-A b+/+ and I-A _b_−/− mice following primary i.n. challenge with the HKx31 influenza virus. Enriched spleen (A and B), MLN (C and D), and BAL (E and F) samples were stained with anti-CD8 antibody and either the DbNP366 or the DbPA224 tetramer. Each data point represents the mean ± SD of values for the spleen samples and pooled MLN and BAL samples for five mice. Similar results were obtained from two further experiments.

FIG. 4.

FIG. 4.

Secondary DbNP366 and DbPA224 epitope-specific CD8+-T-cell responses in the spleen (A and B), MLN (C and D), and BAL (E and F) samples from I-A b+/+ (A, C, and E) and I-A _b_−/− (B, D, and F) mice. The mice had been primed i.p. with the PR8 virus 6 weeks before i.n. challenge with the HKx31 virus. Each data point represents the mean ± SD of values for the spleen samples and pooled MLN and BAL samples for five mice. Similar results were obtained from two further experiments.

FIG. 5.

FIG. 5.

Simulation of infection in I-A b+/+ and I-A _b_−/− hosts according to the mathematical model discussed herein. It is assumed that the I-A _b_−/− mice lacking help from CD4+ T cells differ from the I-A b+/+ controls in two parameters: the rate of expansion (A) and the life span (B) of their CTLs. Both simulations predict similar dynamics. The infection is resolved less efficiently in I-A _b_−/− mice than in I-A b+/+ mice. At the same time, the CTL dynamics are similar in the presence and absence of T-cell help. The chosen values of parameters were as follows: λ was 10; d was 0.1; β was 0.08; a was 0.2; and p was 1. (A) c equals 0.1 in wild-type hosts and 0.05 in mutant hosts; (B) b equals 0.01 in wild-type hosts and 0.1 in mutant hosts.

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