Transient Surface CCR5 Expression by Naive CD8+ T Cells within Inflamed Lymph Nodes Is Dependent on High Endothelial Venule Interaction and Augments Th Cell–Dependent Memory Response

Abstract

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.

CCL3 Enhances Antitumor Immune Priming in the Lymph Node via IFNγ with Dependency on Natural Killer Cells

“…Watanabe and colleagues showed that macrophages pretreated with CCL3 exhibit strengthened adhesion to osteoblasts leading to the formation of pre-osteoclast cells in vitro , an important step in the process of bone reabsorption ( 31 ). Previously, we showed that blocking CCL3 (and its paralog CCL4) in vivo decreased CD8 + T cell and DC contacts in the vaccine-draining LN and diminishes the magnitude of the overall CD8 + T cell memory pool ( 5 ). In two separate studies, Park and colleagues showed that pretreatment of DCs with CCL3 in combination with CCL19 and LPS stimulation led to enhanced OVA-specific CD4 + (OT-II) T cell proliferation in vitro .…”

“…Chemokines are cytokines that function primarily as chemoattractants and help maintain specific immune microenvironments by coordinating various immune cell–cell interactions in a specific spatio-temporal manner. For example, we and others have demonstrated a crucial role for CCL3 and CCL4 in maximizing chance encounters between naïve CCR5 + CD8 + T cells and dendritic cells (DCs) that undergo productive interactions with antigen (Ag)-specific CD4 + or CD8 + T cells in the LN draining vaccine sites ( 3 – 5 ). Furthermore, CCL3 has been shown to be required for maximal helper CD4 + T cell-dependent memory CD8 + T cell generation in the DLN during the initial T cell priming phase ( 3 ).…”

“… Lymph node (LN) plays a critical role in tumor cell survival outside of the primary tumor sites and dictates overall clinical response in many tumor types ( 1 , 2 ). Previously, we and others have demonstrated that CCL3 plays an essential role in orchestrating T cell—antigen-presenting cell (APC) encounters in the draining LN following vaccination, and such interactions enhance the magnitude of the memory T cell pool ( 3 – 5 ). In the current study, we investigate the cellular responses in the tumor-draining lymph nodes (TDLNs) of a CCL3-secreting CT26 colon tumor (L3TU) as compared to wild-type tumor (WTTU) during the priming phase of an antitumor response (≤10 days).…”

Impacts of CCL4 gene polymorphisms on hepatocellular carcinoma susceptibility and development

“…It is possible that the AT and GA haplotypes of CCL4 are in LD with other functional polymorphisms that are responsible for the susceptibility to HCC. It has been reported that CCL4 secretion by CD4+- antigen-presenting cell APC complexes, which correlated with increased cross-priming of CCR5-expressing CD8+ T lymphocytes 32 . Then CD8+ T lymphocytes exit the draining lymph node and migrate to the tumor site, where they exert their cytotoxic function on cancer cells.…”

J AIDS HIV Treat 1.1

“…Elements located in the N-terminus and second ECL of CCR5 are specifically relevant for interactions with HIV-1 during virus entry, putting focus on them as attractive targets for designing more productive antiretroviral therapies. In addition, CCR5 has a further advantage as a cellular target because it is relatively unnecessary for normal immune function, in contrast with receptor CD4 and the viral coreceptor CXCR4 [17]. Both have critical roles in immune function [18,19], which severely limits their utility as antiretroviral therapy targets.…”