How killer cells organize troops in fight against infection
Monday, February 27, 2017
Within days of a viral infection, an army of cytotoxic T cells spreads out to track and kill infected body cells to prevent the further spread of pathogens. Cytotoxic T cells only become active and multiply upon evidence of a pathogen, somewhat like a police dog that springs into action only after it sniffs a piece of the perpetrator's property.
But a new study by an international research team explains one important mechanism behind building this army of killer cells. Researchers at the Institute of Experimental Immunology at the University of Bonn led the study, which involved researchers from the United States, Japan and Germany. The University of Bonn provided support for this study, published in the journal Immunity.
Dendritic cells (DCs) patrol the body, looking for foreign molecules. When a DC finds one, the dendritic cell shows the foreign molecule to the next cytotoxic T cell it can find.
Until now, immunologists thought mere contact with a dendritic cell was enough to activate the killer cell fully. The new study shows that, immediately after contact with and instruction by a dendritic cell, the killer cell creates a team by issuing a chemical help signal to specialized defense cells. These cells then head toward the dendritic cells and, upon arrival, set into motion various immune processes. Activation of the killer cell is complete only after the arrival and activation of this army of specialized defense cells.
There are a number of different killer cells in the body. Each specializes in killing specific foreign substances, and activation only occurs after exposure to those particular substances.
This means it can take some time for the dendritic cell to find an appropriate killer cell. When the dendritic cell encounters an appropriate killer cell, however, things happen quickly. The killer cell divides rapidly to create an army of special forces that aggressively seek out other instances of the pathogen.
These specialized cells begin to divide and differentiate significantly, creating troops of strong but short-lived killer cells, less powerful killer cells that live longer, and even Memory T cells and Memory B cells that activate quickly in the event of another infection from that particular pathogen.
Antigen-specific interactions between T lymphocytes and dendritic cells can initiate adaptive cellular immunity. Plasmacytoid dendritic cells (pDCs) are a specialized type of dendritic cells that can sense viral and bacterial pathogens. Found in circulating blood and peripheral lymphoid organs, pDCs are important drivers in both innate and adaptive immunity. In fact, pDCs support antiviral immunity by linking the two immune responses.
The research team wanted to know what has to occur to help killer cells multiply effectively. Specifically, the focus of the research was to discover when, where, and how pDC spatiotemporal dynamics exert their function during viral infection.
Most killer T cells express T cell receptors (TCRs) that recognize a specific antigen. Inside cells, antigens bind to class I MHC molecules. These class I MCH molecules then bring the antigen to the surface of the cell, where the T cell can recognize them. If the T cell receptor is specific for that antigen, it will bind to the antigen and to the class I MHC molecule. The T cell then kills the cell.
The TCR needs the help of the glycoprotein CD8 to bind to the class I MHC molecule. CD8 binds to the constant portion of the class I MCH molecule to create CD8+ T cells.
The researchers found that plasmacytoid dendritic cells accumulated at the sites of CD8+ T cell antigen-driven activation. They also found that activated CD+T cells recruited XCR1 chemokine receptor-expressing DCs through secretion of the XCL1 chemokine, a type of signaling protein that attracts white blood cells to sites of infection.
Reorganization of the local dendritic cell networks through CD8+ T cell-mediation allows for the interaction of pDCs and XCR1+ DCs, which promote memory CD8+ T cell recall upon secondary infection.
The results suggest that, upon activation, CD8+ T cells recruit additional dendritic cell subsets to the site of initial antigen recognition to create their own optimal priming microenvironment. Creating a specific microenvironment first is critical for a strong, coordinated immune defense mechanism.
The information provided in this study may someday help improve the effectiveness of vaccines against viruses or tumors.
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