Chemokines control naive CD8(+) T cell selection of optimal lymph node antigen presenting cells

Cell Biology and Viral Immunology Sections, Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Journal of Experimental Medicine (Impact Factor: 12.52). 11/2011; 208(12):2511-24. DOI: 10.1084/jem.20102545
Source: PubMed


Naive antiviral CD8(+) T cells are activated in the draining LN (DLN) by dendritic cells (DCs) presenting viral antigens. However, many viruses infect LN macrophages, which participate in initiation of innate immunity and B cell activation. To better understand how and why T cells select infected DCs rather than macrophages, we performed intravital microscopy and ex vivo analyses after infecting mice with vaccinia virus (VV), a large DNA virus that infects both LN macrophages and DCs. Although CD8(+) T cells interact with both infected macrophages and DCs in the LN peripheral interfollicular region (PIR), DCs generate more frequent and stable interactions with T cells. VV infection induces rapid release of CCR5-binding chemokines in the LN, and administration of chemokine-neutralizing antibodies diminishes T cell activation by increasing T cell localization to macrophages in the macrophage-rich region (MRR) at the expense of PIR DCs. Similarly, DC ablation increases both T cell localization to the MRR and the duration of T cell-macrophage contacts, resulting in suboptimal T cell activation. Thus, virus-induced chemokines in DLNs enable antiviral CD8(+) T cells to distinguish DCs from macrophages to optimize T cell priming.

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    • "This promotes sustained contacts between CD8 þ T cells and the CD4 þ licensed DCs, which is necessary for optimal CD8 þ Tcell memory responses. However, the precise role for CCR5 remains unclear as viral infection models using different vaccinia virus strains have shown contradictory results for the role of CCR5 in CD8 þ T-cell priming (Hickman et al. 2011; Kastenmuller et al. 2013). Finally, in a model of CD8 þ T-cell priming using injection of a-galactosylceramide, CCR4 signaling promoted stable contacts between CD8 þ T cells and DCs (Semmling et al. 2010). "
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    • "Since naïve T cells are largely located in the LN cortex where they continuously scan DCs, it was tempting to assume that following infection, T cell priming would occur deep in the LN cortex. However, in vivo visualization of early T cell–APC interactions immediately following viral infections revealed that T cell priming in fact occurred near the cortical ridge or at the interfollicular region of the dLN (32, 63–65). Subcutaneous infection with vaccinia virus or vesicular stomatitis virus (VSV) resulted in the infection of macrophages and DCs present in the LN subcapsular sinus (SCS), however, only DCs that expressed virus encoded protein appeared to present antigen directly to transferred TCR transgenic CD8 T cells (32, 63, 65). "
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