Human T cells efficiently control RSV infection
Chandrav De, Raymond J. Pickles, Wenbo Yao, Baolin Liao, Allison Boone, Mingyu Choi, Diana M. Battaglia, Frederic B. Askin, Jason K. Whitmire, Guido Silvestri, J. Victor Garcia, Angela Wahl
Chandrav De, Raymond J. Pickles, Wenbo Yao, Baolin Liao, Allison Boone, Mingyu Choi, Diana M. Battaglia, Frederic B. Askin, Jason K. Whitmire, Guido Silvestri, J. Victor Garcia, Angela Wahl
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Research Article Immunology Virology

Human T cells efficiently control RSV infection

Abstract

Respiratory syncytial virus (RSV) infection causes significant morbidity and mortality in infants, immunocompromised individuals, and older individuals. There is an urgent need for effective antivirals and vaccines for high-risk individuals. We used 2 complementary in vivo models to analyze RSV-associated human lung pathology and human immune correlates of protection. RSV infection resulted in widespread human lung epithelial damage, a proinflammatory innate immune response, and elicited a natural adaptive human immune response that conferred protective immunity. We demonstrated a key role for human T cells in controlling RSV infection. Specifically, primed human CD8+ T cells or CD4+ T cells effectively and independently control RSV replication in human lung tissue in the absence of an RSV-specific antibody response. These preclinical data support the development of RSV vaccines, which also elicit effective T cell responses to improve RSV vaccine efficacy.

Authors

Chandrav De, Raymond J. Pickles, Wenbo Yao, Baolin Liao, Allison Boone, Mingyu Choi, Diana M. Battaglia, Frederic B. Askin, Jason K. Whitmire, Guido Silvestri, J. Victor Garcia, Angela Wahl

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Figure 4

Human CD8+ T cell depletion impairs but does not eliminate the control of RSV replication in vivo.

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Human CD8+ T cell depletion impairs but does not eliminate the control o...
(A) Experimental diagram to evaluate the effect of CD8+ T cell depletion on RSV replication. LoM and BLT-L mice administered placebo or CD8-depleting antibody (3 mg/kg, i.v.) were exposed to RSV-Luc and, 21 days later, rechallenged with RSV-Luc. CD8+ T cell depletion was confirmed in blood and tissues (Supplemental Figure 3). (B and C) RSV replication was monitored in the lung implants of LoM (blue boxes, n = 10 implants), placebo-treated BLT-L mice (red boxes, n = 12 implants), and CD8-depleted BLT-L mice (gray boxes, n = 10 implants) following the (B) first and (C) second RSV exposure by measuring the bioluminescence signal (radiance [p sec–1 cm–2 sr–1] represented as total flux). The median (horizontal line), upper and lower quartiles (box ends), and minimum to maximum values (whiskers) are shown. (D) RSV antigen (brown) in the lung implants of LoM, placebo-treated BLT-L mice, and CD8-depleted BLT-L mice 14 days after the second exposure (n = 6 implants analyzed). Scale bars: 100 μm. (E) H&E staining of the lung implants of naive (n = 5 implants analyzed), placebo-treated (n = 4 implants analyzed), or CD8-depleted (n = 8 implants analyzed) BLT-L mice. Scale bars: 100 μm. Arrow indicates fibrin in airway lumen. (F) CD4+ and CD8+ T cell numbers (left) and activated (CD38+HLA-DR+) CD4+ and CD8+ T cell levels (right) in the lung implants of naive BLT-L mice (green; T cell levels, n = 8 implants; activation levels, n = 7 implants) and in placebo-treated (red, n = 10 implants) and CD8-depleted (gray, n = 10 implants) BLT-L mice 14 days after the second RSV exposure. Data are shown as mean ± SEM. Statistical significance was determined with a 2-tailed (B, C, and E) Kruskal-Wallis or (E) Mann-Whitney U test. P values were adjusted for multiple testing using the Benjamini, Krieger, and Yekutieli FDR method.