Naïve T cells continually recirculate between blood and secondary lymphoid organs, scanning dendritic cells (DC) for foreign antigen. Despite its importance for understanding how adaptive immune responses are efficiently initiated from rare precursors, a detailed quantitative analysis of this fundamental process has not been reported. Here we measure lymph node (LN) entry, transit, and exit rates for naïve CD4 + and CD8 + T cells, then use intravital imaging and mathematical modeling to relate cell-cell interaction dynamics to population behavior. Our studies reveal marked differences between CD4 + vs. CD8 + T cells. CD4 + T cells recirculate more rapidly, homing to LNs more efficiently, traversing LNs twice as quickly, and spending ∼1/3 of their transit time interacting with MHCII on DC. In contrast, adoptively transferred CD8 + T cells enter and leave the LN more slowly, with a transit time unaffected by the absence of MHCI molecules on host cells. Together, these data reveal an unexpectedly asymmetric role for MHC interactions in controlling CD4 + vs. CD8 + T lymphocyte recirculation, as well as distinct contributions of T cell receptor (TCR)-independent factors to the LN transit time, exposing the divergent surveillance strategies used by the two lymphocyte populations in scanning for foreign antigen.trafficking | migration | immune recognition P eripheral naïve CD4 + and CD8 + T cells lead a nomadic existence, circulating between blood, secondary lymphoid organs (SLOs), and lymph in search of foreign antigen and survival signals (1, 2). Factors affecting T-cell entry into lymph nodes (LN) across vascular endothelium are well characterized. L-Selectin (CD62L) enables the initial rolling of T cells along high endothelial venules (HEV), whereas chemokine (C-C motif) receptor 7 (CCR7) signaling upon binding of its ligands CCL19 and CCL21 activates the integrins α L β 2 (LFA-1) and α 4 β 1 (VLA-4), facilitating their firm adhesion and transendothelial migration (1). T cells are extremely dynamic after entering SLOs, moving along the fibroblastic reticular cell network at average speeds of ∼11 μm/min (3, 4). In contrast, the temporal and spatial dynamics of distinct T-cell populations as they traverse SLOs after such endothelial transmigration, the influence of this migratory behavior on efficient scanning of the body for invasion by infectious agents, and the factors that influence motility, residence time, and egress rates from SLOs of these highly motile T cells are largely unexplored or just beginning to be understood (5).A key step in developing a dynamic understanding of lymphocyte percolation through LNs is to measure how long different T-cell subsets spend in an SLO before egressing into lymph. To date, only expression of CCR7 and Sphingosine-1-phosphate receptor 1 (S1PR1) has been shown to affect the time spent by T cells within LNs. CCR7 promotes retention, whereas S1PR1 expression is essential to overcome this retention signal and promote egress into the efferent lymph (6). In addition to these chemota...

Polyphenols are natural compounds capable of interfering with the inflammatory pathways of several in vitro model systems. In this study, we developed a stable and effective strategy to administer polyphenols to treat in vivo models of acute intestinal inflammation. The in vitro suppressive properties of several polyphenols were first tested and compared for dendritic cells (DCs) production of inflammatory cytokines. A combination of the polyphenols, quercetin and piperine, were then encapsulated into reconstituted oil bodies (OBs) in order to increase their stability. Our results showed that administration of low dose reconstituted polyphenol OBs inhibited LPS-mediated inflammatory cytokine secretion, including IL-6, IL-23, and IL-12, while increasing IL-10 and IL-1Rα production. Mice treated with the polyphenol-containing reconstituted OBs (ROBs) were partially protected from dextran sodium sulfate (DSS)-induced colitis and associated weight loss, while mortality and inflammatory scores revealed an overall anti-inflammatory effect that was likely mediated by impaired DC immune responses. Our study indicates that the administration of reconstituted quercetin and piperine-containing OBs may represent an effective and potent anti-inflammatory strategy to treat acute intestinal inflammation.

In inflamed lymph nodes, Ag-specific CD4+ and CD8+ T cells encounter Ag-bearing DCs and, together, this complex enhances the release of CCL3 and CCL4 that facilitate additional interaction with naïve CD8+ T cells. While blocking CCL3 and CCL4 has no effect on primary CD8+ T cell responses, it dramatically impairs the development of memory CD8+ T cell upon Ag re-challenge. Despite the absence of detectable surface CCR5 expression on circulating native CD8+ T cells, these data imply that naïve CD8+ T cells are capable of expressing surface CCR5 prior to cognate antigen-induced TCR signaling in inflamed lymph nodes; however, the molecular mechanisms have not been characterized to date. Here, we show that CCR5, the receptor for CCL3 and CCL4, can be transiently upregulated on a subset of naïve CD8+ T cells and this upregulation is dependent on direct contact with the HEV in inflamed lymph node (LN)3. Binding of CD62L and CD11a on T cells to their ligands CD34 and CD54 on the HEV can be enhanced during inflammation. This enhanced binding and subsequent signaling promote the translocation of CCR5 molecules from intracellular vesicles to the surface of the CD8+ T cell. The upregulation of CCR5 on the surface of the CD8+ T cells increases the number of contacts with antigen-bearing DCs, which ultimately results in increased CD8+ T cell response to Ag re-challenge.