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author:("skin, Cara N.")
1.  Transcriptional downregulation of S1pr1 is required for establishment of resident memory CD8+ T cells 
Nature immunology  2013;14(12):10.1038/ni.2745.
Cell-mediated immunity critically depends on lymphocyte localization at sites of infection. While some memory T cells recirculate, a distinct lineage (resident memory T cells; TRM) are embedded in non-lymphoid tissues (NLTs) and mediate potent protective immunity. However, the defining transcriptional basis for TRM establishment is unknown. We report that CD8+ TRM cells lacked expression of the transcription factor KLF2 and its target gene S1pr1 (encoding sphingosine 1-phosphate receptor 1). Forced S1PR1 expression prevented establishment of TRM. Cytokines inducing TRM phenotype (including TGF-β, IL-33 and TNF) provoked KLF2 downregulation in a phosphatidylinositol-3-OH kinase (PI(3)K)–Akt-dependent pathway, suggesting environmental regulation. Hence KLF2 and S1PR1 regulation provides a switch, dictating whether CD8+ T cells commit to the recirculating or tissue resident memory populations.
PMCID: PMC3844557  PMID: 24162775
2.  Intravascular staining redefines lung CD8 T cell responses1 
Non-lymphoid T cell populations control local infections and also contribute to inflammatory diseases, thus driving efforts to understand the regulation of their migration, differentiation, and maintenance. Numerous observations indicate that T cell trafficking and differentiation within the lung is starkly different than what has been described in most non-lymphoid tissues, including intestine and skin. We found that >95% of memory CD8 T cells isolated from mouse lung via standard methods were actually confined to the pulmonary vasculature, despite perfusion. Respiratory route of challenge increased virus specific T cell localization within lung tissue, although only transiently. Removing blood-born cells from analysis by the simple technique of intravascular staining revealed distinct phenotypic signatures and chemokine-dependent trafficking that was restricted to antigen-experienced T cells. These results precipitate a revised model for pulmonary T cell trafficking and differentiation and a re-evaluation of studies examining the contributions of pulmonary T cells to protection and disease.
PMCID: PMC3436991  PMID: 22896631
3.  Chemokines control naive CD8+ T cell selection of optimal lymph node antigen presenting cells 
The Journal of Experimental Medicine  2011;208(12):2511-2524.
CCR5-binding chemokines produced in the draining lymph node after vaccinia virus infection guide naive CD8+ T cells toward DCs and away from the macrophage-rich zone, thereby facilitating optimal CD8+ T cell activation and cytokine production.
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.
PMCID: PMC3256957  PMID: 22042976
4.  Unexpected Role for the Immunoproteasome Subunit LMP2 in Antiviral Humoral and Innate Immune Responses 
Proteasomes are multisubunit proteases that initiate degradation of many Ags presented by MHC class I molecules. Vertebrates express alternate forms of each of the three catalytic proteasome subunits: standard subunits, and immunosubunits, which are constitutively expressed by APCs and are induced in other cell types by exposure to cytokines. The assembly of mixed proteasomes containing standard subunits and immunosubunits is regulated in a tissue specific manner. In this study, we report that the presence of mixed proteasomes in immune cells in LMP2−/− mice compromises multiple components that contribute to the generation of antiviral Ab responses, including splenic B cell numbers, survival and function of adoptively transferred B cells, Th cell function, and dendritic cell secretion of IL-6, TNF-α, IL-1β, and type I IFNs. These defects did not result from compromised overall protein degradation, rather they were associated with altered NF-κB activity. These findings demonstrate an important role for immunoproteasomes in immune cell function beyond their contribution to Ag processing.
PMCID: PMC2941094  PMID: 20228196

Results 1-4 (4)