Dynamic Interplay among Monocyte-Derived, Dermal, and Resident Lymph Node Dendritic Cells during the Generation of Vaccine Immunity to Fungi

Cell and Molecular Pathology Graduate Training Program, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792, USA.
Cell host & microbe (Impact Factor: 12.33). 06/2010; 7(6):474-87. DOI: 10.1016/j.chom.2010.05.010
Source: PubMed


Early innate events that enable priming of antifungal CD4 T cells are poorly understood. We engineered an attenuated fungal vaccine with a model epitope, EalphaRFP, to track vaccine immunity to Blastomyces dermatitidis during yeast recognition, antigen presentation, and priming of naive T cells. After subcutaneous injection of the vaccine, monocyte-derived inflammatory dendritic cells (DCs) are the earliest and largest population that associates with yeast, carrying them into the draining lymph nodes. Despite marked association with yeast, these DCs fail to display surface peptide:MHC complexes or prime naive T cells. Instead, the ability to display antigen and prime CD4 T cells resides with lymph node-resident DCs after antigen transfer from immigrant DCs and with skin migratory DCs. Our work reveals the dynamic interplay among distinct DC subsets that prime naive CD4 T cells after yeast are injected in the skin and discloses the cellular elements underlying vaccine-induced immunity to fungi.

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    • "However, it is less obvious in the case of bona fide cDC immigrants, which are themselves considered fully capable to prime T cells. Specific Ag transfer from moDCs to resident cDCs for naive CD4 + T priming was also observed in yeast-infected animals (Ersland et al., 2010). Thus, cell-tocell Ag transfer might be a more common theme to be explored in the future. "
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    • "InfDCs can be modeled in vitro by bone-marrow derived DCs (BM-DC) cultured with GM-CSF (Xu et al., 2007), although GM-CSF seems dispensable for their development in vivo (Greter et al., 2012). InfDCs migrate to lymphoid organs where they can present antigens to both CD4 + and CD8 + T cells (Ballesteros-Tato et al., 2010; Hammad et al., 2010; Leó n et al., 2007) or transfer antigens to resident DCs (Ersland et al., 2010). In addition, infDCs can activate memory T cells directly in peripheral tissues (Wakim et al., 2008). "
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    • "Although Ly6C hi monocytes carry Bd yeast into the sdLNs after s.c. vaccination (Ersland et al., 2010), in Ccr2 −/− mice lacking Ly6C hi DCs, other migratory skin and resident DCs compensate by delivering yeast into the draining nodes to prime T cells. In contrast, during mucosal vaccine delivery here, the modulation of Ly6C hi monocyte influx – either due to Bd alone or in mixed infection, or in Ccr2 −/− mice – sharply reduced the numbers of vaccine yeast delivered to the MLN and impaired priming of T cells. "
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    ABSTRACT: Vaccinologists strive to harness immunity at mucosal sites of pathogen entry. We studied respiratory delivery of an attenuated vaccine against Blastomyces dermatitidis. We created a T cell receptor transgenic mouse responsive to vaccine yeast and found that mucosal vaccination led to poor T cell activation in the draining nodes and differentiation in the lung. Mucosal vaccination subverted lung T cell priming by inducing matrix metalloproteinase 2 (MMP2), which impaired the action of the chemokine CCL7 on egress of CCR2(+) Ly6C(hi) inflammatory monocytes from the bone marrow and their recruitment to the lung. Studies in Mmp2(-/-) mice, or treatment with MMP inhibitor or rCCL7, restored recruitment of Ly6C(hi) monocytes to the lung and CD4(+) T cell priming. Mucosal vaccination against fungi and perhaps other respiratory pathogens may require manipulation of host MMPs in order to alter chemokine signals needed to recruit Ly6C(hi) monocytes and prime T cells at the respiratory mucosa.
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