Stem cell transplantation impairs dendritic cell trafficking and herpesvirus immunity
Carol A. Wilke, Mathew M. Chadwick, Paul R. Chan, Bethany B. Moore, Xiaofeng Zhou
Carol A. Wilke, Mathew M. Chadwick, Paul R. Chan, Bethany B. Moore, Xiaofeng Zhou
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Research Article Immunology Inflammation

Stem cell transplantation impairs dendritic cell trafficking and herpesvirus immunity

Abstract

Long-term survivors after hematopoietic stem cell transplantation are at high risk of infection, which accounts for one-third of all deaths related to stem cell transplantation. Little is known about the cause of inferior host defense after immune cell reconstitution. Here, we exploited a murine syngeneic BM transplantation (BMT) model of late infection with murine gammaherpesvirus 68 (MHV-68) to determine the role of conventional DC (cDC) trafficking in adaptive immunity in BMT mice. After infection, the expression of chemokine Ccl21 in the lung is reduced and the migration of cDCs into lung draining lymph nodes (dLNs) is impaired in BMT mice, limiting the opportunity for cDCs to prime Th cells in the dLNs. While cDC subsets are redundant in priming Th1 cells, Notch2 functions in cDC2s are required for priming increased Th17 responses in BMT mice, and cDC1s can lessen this activity. Importantly, Th17 cells can be primed both in the lungs and dLNs, allowing for increased Th17 responses without optimum cDC trafficking in BMT mice. Taken together, impaired cDC trafficking in BMT mice reduces protective Th1 responses and allows increased pathogenic Th17 responses. Thus, we have revealed a previously unknown mechanism for BMT procedures to cause long-term inferior immune responses to herpes viral infection.

Authors

Carol A. Wilke, Mathew M. Chadwick, Paul R. Chan, Bethany B. Moore, Xiaofeng Zhou

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Figure 1

APCs from lungs of BMT mice are potent in priming both Th1 and Th17 responses in vitro.

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APCs from lungs of BMT mice are potent in priming both Th1 and Th17 resp...
(A) Single-cell suspensions were prepared by collagenase digestion of whole lungs of non-BMT (n = 5) or BMT (n = 5) mice at 7 dpi with MHV-68. Cells were then stimulated with PMA and ionomycin for 4 hours before antibody staining. Percent of CD4+ T cells (i.e., CD45+CD90.2+CD3+CD4+) that express IFN-γ (Th1 cells), and percent of CD4+ T cells that express IL-17A (Th17 cells) were determined by flow cytometry. (B and C) APCs enriched by CD11c+ microbeads and pooled from lung Single-cell suspensions of 5 BMT or non-BMT mice at 3 dpi were cocultured with pooled CD4+ T cells from 10 BMT mouse lungs at 10 dpi at a 1:10 ratio in the presence of 0.125 MOI of MHV-68 (n = 5 each). (B) The concentration of IFN-γ or IL-17A in the supernatant of coculture at 4 days was determined by ELISA (mean ± SEM, n = 5). (C) Cocultured cells were pelleted at 4 days after coculture, and total RNA was isolated by TRIzol. The expression of a pro-Th1 cytokine (IL12A) or pro-Th17 cytokines (IL6 and IL23A) were determined by real-time RT-PCR (mean ± SEM, n = 5). Symbols represent individual data points from unique mice. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001, Student’s t test (2 tailed). Similar results were obtained in 2 additional experiments. APCs, antigen-presenting cells; BMT, BM transplantation.