Diminished primary and secondary influenza virus-specific CD8(+) T-cell responses in CD4-depleted Ig(-/-) mice

Abstract

Optimal expansion of influenza virus nucleoprotein (D(b)NP(366))-specific CD8(+) T cells following respiratory challenge of naive Ig(-/-) microMT mice was found to require CD4(+) T-cell help, and this effect was also observed in primed animals. Absence of the CD4(+) population was consistently correlated with diminished recruitment of virus-specific CD8(+) T cells to the infected lung, delayed virus clearance, and increased morbidity. The splenic CD8(+) set generated during the recall response in Ig(-/-) mice primed at least 6 months previously showed a normal profile of gamma interferon production subsequent to short-term, in vitro stimulation with viral peptide, irrespective of a concurrent CD4(+) T-cell response. Both the magnitude and the localization profiles of virus-specific CD8(+) T cells, though perhaps not their functional characteristics, are thus modified in mice lacking CD4(+) T cells.

FIG. 1

Virus titers in lung homogenates (log₁₀ EID₅₀/100 μl) recovered from Ig^−/− μMT mice during a primary or secondary response in the presence or absence of CD4⁺ T cells. The secondary-challenge mice (5) were primed more than 1 month previously with either the PR8 (H1N1) (A) or HKx31 (H3N2) (B) influenza A virus and then challenged i.n. with the H3N2 virus. Some (−CD4) were depleted of CD4⁺ T cells (2), while others (control) were treated with an irrelevant MAb. Groups of four to five mice were assayed at each time point, and the results are expressed as mean ± standard deviation. The secondary response was not assayed on day 11. The “0” results are included to show that the mice were sampled, but no virus was recovered.

FIG. 2

The primary and secondary CD8⁺ T-cell response to D^bNP₃₆₆ in control and CD4-depleted Ig^−/− μMT mice. The secondary-challenge mice (4) were primed more than 1 month previously with either the PR8 (H1N1; (A to C) or HKx31 (H3N2; D to F) influenza A virus and then challenged i.n. with the H3N2 virus. These are the same experiments as those illustrated in Fig. 1, which gives virus titers in lungs. The BAL populations (A and D) were pooled, and the spleen (B and E) and MLN (C and F) samples (mean ± standard deviation) were assayed as individuals. The numbers of virus-specific CD8⁺ T cells were calculated from the percent staining for both CD8α and D^bNP₃₆₆ and the total cell counts (5).