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. 2008 Apr;82(8):4115-24.
doi: 10.1128/JVI.02313-07. Epub 2008 Feb 13.

The role of T cells in the enhancement of respiratory syncytial virus infection severity during adult reinfection of neonatally sensitized mice

John S Tregoning  1 , Yuko Yamaguchi, James Harker, Belinda Wang, Peter J M Openshaw
Affiliations

The role of T cells in the enhancement of respiratory syncytial virus infection severity during adult reinfection of neonatally sensitized mice

John S Tregoning et al. J Virol. 2008 Apr.

Abstract

Respiratory syncytial virus (RSV) is the major cause of infantile bronchiolitis and hospitalization. Severe RSV disease is associated with the development of wheezing in later life. In a mouse model of the delayed effects of RSV, the age at primary infection determines responses to reinfection in adulthood. During primary RSV infection, neonatal BALB/c mice developed only mild disease and recruited CD8 cells that were defective in gamma interferon production. Secondary reinfection of neonatally primed mice caused enhanced inflammation and profuse lung T-cell recruitment. CD4 cell depletion during secondary RSV challenge attenuated disease (measured by weight loss); depletion of CD8 cells also markedly attenuated disease severity but enhanced lung eosinophilia, and depletion of both CD4 and CD8 cells together completely abrogated weight loss. Depletion of CD8 (but not CD4) cells during primary neonatal infection was protective against weight loss during adult challenge. Therefore, T cells, in particular CD8 T cells, play a central role in the outcome of neonatal infection by enhancing disease during secondary challenge. These findings demonstrate a crucial role for T cells in the regulation of immune responses after neonatal infection.

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Figures

FIG. 1.
FIG. 1.
Primary RSV infection is more severe in adult mice than in neonates. Mice were i.n. infected neonatally (age, 4 days) or as immature adults (age, 4 to 6 weeks) with 4 × 104 PFU RSV per gram body weight. (A and B) Graphs show changes in body weight after the primary RSV or mock infection (Control) in neonatal (A) and adult (B) mice. (C and D) Lung cell counts p.i. in neonatal (C) and adult (D) mice after RSV infection or mock infection. (E to H) H&E-stained, formalin-fixed-lung histology sections at day 7 (d7) posttreatment in neonatal or adult mice (controls, E and F; RSV-infected mice, G and H). There were at least four mice per group. Data are means ± SEM. *, P < 0.05; **, P < 0.01; ***, P < 0.001.
FIG. 2.
FIG. 2.
Dynamic changes in lungs after primary RSV infection. Neonatal and adult mice were infected as described in the legend for Fig. 1, and lungs were harvested at days 4, 7, 11, and 14 after the primary infection. (A and B) Cell types in the lung (CD4 T-cell effector memory types [CD44 hi and CD62L lo] [A] and CD8 T-cell effector memory types [CD44 hi and CD62L lo] [B]) were assessed by flow cytometry. (C) CCL5 in lung digests was measured by ELISA. (D to F) RSV (M2) pentamer-positive CD8 T cells, sample plots from neonatal (D) and adult (E) mice on day 11 and time course (F). (G to I) RSV (M2) peptide-specific IFN-γ-producing CD8 T cells measured by intracellular staining, sample plots from neonatal (G) and adult (H) mice on day 11 and time course (I). There were at least four mice per group. Data are means ± SEM. *, P < 0.05; **, P < 0.01; ***, P < 0.001.
FIG. 3.
FIG. 3.
Timing of primary RSV infection determines the effect of adult rechallenge. Mice were infected with RSV at the age of 4 days (Neonatal) or as adults (age, 4 weeks) and challenged with 5 × 105 PFU RSV at 8 weeks old. (A and B) Changes in body weight (A) and baseline Penh (B) after secondary infection; (C) lung cell counts; (D) BAL granulocyte counts; (E) chemokine levels; (F) lung CD4 and CD8 T cell counts; (G and H) percentages of CD4 (G) and CD8 (H) cells positive for IFN-γ, TNF, and IL-4 at day 7 p.i. (d7). There were at least four mice per group. Data are means ± SEM. *, P < 0.05; **, P < 0.01; ***, P < 0.001.
FIG. 4.
FIG. 4.
Neonatal RSV infection induces inflammation and goblet cell hyperplasia following secondary RSV challenge. Mice were infected as adults or neonates and rechallenged 8 weeks later as described for Fig. 3. Representative H&E-stained (A to D) and periodic acid-Schiff-stained (PAS) (E to H), formalin-fixed lung sections taken on day 4 (d4) and day 7 after adult challenge. The scale bar represents 20 μm. (I to L) Fivefold enlargements of regions with goblet cells are shown.
FIG. 5.
FIG. 5.
Depletion of T lymphocytes during primary RSV infection reduces lung inflammation. During primary RSV infection, adult mice were treated i.p. with T-cell-depleting antibodies on days −1, +2, and +5 of infection. (A) Weight change after RSV infection. (B and C) Lung cell numbers (B) and T-cell numbers (C) on day 7 after RSV infection. (D and E) Neutrophilia (D) and KC level (E) measured in BAL fluid 7 days after RSV infection. There were four mice per group. Data are means ± SEM. ***, P < 0.001.
FIG. 6.
FIG. 6.
Depletion of T lymphocytes during secondary RSV challenge reduces lung inflammation. Mice were infected at 4 days of age (primary infection [1o]) and rechallenged at 8 weeks (secondary infection [2o]). (A) During secondary RSV challenge, mice were treated i.p. with T-cell-depleting antibodies (Ab) according to the treatment schedule. d, day. (B) Weight change after secondary RSV challenge. NN, neonates. (C) Lung viral load 4 days after secondary challenge. (D and E) Lung cell numbers (D) and T-cell numbers (E) on day 7 after RSV challenge. (E to I) Eosinophilia (F), CCL11 (G), neutrophilia (H), and KC (I) levels were measured in BAL fluid 7 days after the secondary RSV challenge. There were at least four mice per group. Data are means ± SEM. *, P < 0.05; **, P < 0.01; ***, P < 0.001.
FIG. 7.
FIG. 7.
Depletion of CD8 cells during primary neonatal RSV infection (1o) affects the outcome of adult rechallenge. Mice were infected with RSV as neonates (NN) and challenged 8 weeks later with RSV (secondary infection [2o]). (A) During primary neonatal RSV infection, mice were treated i.p. with T-cell-depleting antibodies (Ab) according to the treatment schedule. d, day. (B) Weight change after secondary RSV challenge. (C) Lung viral loads at day 4 p.i. (D to I) BAL cell numbers (D), lung T-cell numbers (E), eosinophilia (F), CCL11 levels (G), neutrophilia (H), and KC levels (I) measured in BAL fluid 7 days after secondary RSV challenge. There were at least four mice per group. Data are means ± SEM. *, P < 0.05.
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References

    1. Adkins, B., C. LeClerc, and S. Marshall-Clarke. 2004. Neonatal adaptive immunity comes of age. Nat. Rev. Immunol. 4553-564. - PubMed
    1. Alwan, W. H., F. M. Record, and P. J. M. Openshaw. 1992. CD4+ T cells clear virus but augment disease in mice infected with respiratory syncytial virus: comparison with the effects of CD8+ cells. Clin. Exp. Immunol. 88527-536. - PMC - PubMed
    1. Bisgaard, H., M. N. Hermansen, F. Buchvald, L. Loland, L. B. Halkjaer, K. Bonnelykke, M. Brasholt, A. Heltberg, N. H. Vissing, S. V. Thorsen, M. Stage, and C. B. Pipper. 2007. Childhood asthma after bacterial colonization of the airway in neonates. N. Engl. J. Med. 3571487-1495. - PubMed
    1. Bonhoeffer, J., C. A. Siegrist, and P. T. Heath. 2006. Immunisation of premature infants. Arch. Dis. Child. 91929-935. - PMC - PubMed
    1. Chang, J., and T. J. Braciale. 2002. Respiratory syncytial virus infection suppresses lung CD8+ T-cell effector activity and peripheral CD8+ T-cell memory in the respiratory tract. Nat. Med. 854-60. - PubMed

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