Led by immunologist Ronald Germain, M.D., Ph.D., the scientists took videos through a microscope to document what happens inside the lymph nodes of a living mouse shortly after a vaccination. The videos reveal that the movement of a specific type of immune cell known as a CD8+ T cell, also called a cytotoxic T cell, is not random as was previously thought, but instead is guided by chemical signals released from other cells.
Scientists have long recognized the importance of understanding how CD8+ T cells move through the lymph nodes and become activated. Once active, CD8+ T cells roam throughout the body destroying cells infected with bacteria or viruses--a process known as cell-mediated immunity. When these CD8+ T cells encounter an infected cell, they unleash a torrent of substances that poke holes in the cell’s membrane, chew up its proteins and ultimately cause it to die. They also produce molecules such as interferon-gamma that help activate other immune cells.
After they fight the initial infection, some of these CD8+ T cells remain in the circulation as memory cells, primed to fight if the host is re-infected with the same pathogen. Memory cells are key to vaccine strategies being studied for infectious agents such as HIV. But the CD8+ T cells can only become effective, long-lived memory cells after they encounter certain other cells in the lymph node that can activate them.
The new research, conducted largely by senior postdoctoral fellows Flora Castellino, M.D., and Alex Huang, M.D., Ph.D., with Dr. Germain’s guidance, shows that when CD8+ T cells enter the lymph node, a combination of specific physical and chemical cues guides them to sites where they receive activation signals. Specifically, two molecules known as chemokines help guide them toward the cells that release these activation signals.
"Understanding the processes whereby CD8+ T cells find their way in the lymph nodes is important because their activation is essential for eliminating infected cells and for providing, together with antibodies, long-lasting protection following vaccinations," says NIAID Director Anthony S. Fauci, M.D.
The body contains hundreds of millions of CD8+ T cells, but only a tiny fraction of them become activated during an infection. These are selected because each CD8+ T cell carries a unique surface protein called a T-cell receptor, which recognizes only specific antigens (pieces of virus or bacteria that trigger the immune response). During an infection, CD8+ T cells that recognize antigens from the infecting pathogen are activated. These antigen-specific CD8+ T cells expand into a large population of active clones, which then sweep through the body, hunting down and killing infected cells.
For CD8+ T-cell activation to occur in the lymph node, the cell must encounter its target antigen--but that antigen must be displayed on the surface of another immune system cell, called a dendritic cell. Usually a third type of cell, known as a "helper" T cell, must be involved as well. But how do the CD8+ T cells find the right dendritic cells presenting the specific antigen they need to see? Moreover, how do they find the particular dendritic cells that have been properly stimulated by helper T cells?
Dr. Germain and his colleagues determined that naïve CD8+ T cells do not wander aimlessly through the lymph node but instead are steered towards areas in which dendritic cells concentrate. Think of the lymph node as a large airport terminal and the CD8+ T cells as the arriving passengers, says Dr. Germain. If passengers know that limo drivers will meet them in the terminal, they will look for their drivers upon arrival. Rather than hoping to run into each other by chance, the drivers crowd around the arrival gates and hold up signs that the passengers can read from a distance.
Moreover, CD8+ T cells are chemically attracted to the cells that might activate them by the chemokines these other cells produce. Dr. Germain and his colleagues demonstrated that when CD8+ T cells enter the lymph nodes and detect a potential infection, they express receptors that allow them to detect and follow these chemokines.
The NIAID team also showed that when dendritic cells interact in specific fashion with helper T cells, the activated cell pair releases the chemokines CCL3 and CCL4. It is the combination of these two chemokines that the CD8+ T cells receive best as a signal, says Dr. Germain. By interfering with the action of these chemokines, he and his colleagues demonstrated that CD8+ T cells lost their ability to home in on the dendritic cells interacting with the helper T cells. The result was a marked impairment of memory cell generation.
These new findings not only provide insight into the fundamental behavior of the immune system, but also suggest that attention needs to be paid to chemokines and chemokine receptor function when designing new vaccine strategies and evaluating whether drugs targeting chemokines might have unanticipated effects on immune function.
Jason Socrates Bardi | EurekAlert!
A Map of the Cell’s Power Station
18.08.2017 | Albert-Ludwigs-Universität Freiburg im Breisgau
On the way to developing a new active ingredient against chronic infections
18.08.2017 | Deutsches Zentrum für Infektionsforschung
Whether you call it effervescent, fizzy, or sparkling, carbonated water is making a comeback as a beverage. Aside from quenching thirst, researchers at the University of Illinois at Urbana-Champaign have discovered a new use for these "bubbly" concoctions that will have major impact on the manufacturer of the world's thinnest, flattest, and one most useful materials -- graphene.
As graphene's popularity grows as an advanced "wonder" material, the speed and quality at which it can be manufactured will be paramount. With that in mind,...
Physicists at the University of Bonn have managed to create optical hollows and more complex patterns into which the light of a Bose-Einstein condensate flows. The creation of such highly low-loss structures for light is a prerequisite for complex light circuits, such as for quantum information processing for a new generation of computers. The researchers are now presenting their results in the journal Nature Photonics.
Light particles (photons) occur as tiny, indivisible portions. Many thousands of these light portions can be merged to form a single super-photon if they are...
For the first time, scientists have shown that circular RNA is linked to brain function. When a RNA molecule called Cdr1as was deleted from the genome of mice, the animals had problems filtering out unnecessary information – like patients suffering from neuropsychiatric disorders.
While hundreds of circular RNAs (circRNAs) are abundant in mammalian brains, one big question has remained unanswered: What are they actually good for? In the...
An experimental small satellite has successfully collected and delivered data on a key measurement for predicting changes in Earth's climate.
The Radiometer Assessment using Vertically Aligned Nanotubes (RAVAN) CubeSat was launched into low-Earth orbit on Nov. 11, 2016, in order to test new...
A study led by scientists of the Max Planck Institute for the Structure and Dynamics of Matter (MPSD) at the Center for Free-Electron Laser Science in Hamburg presents evidence of the coexistence of superconductivity and “charge-density-waves” in compounds of the poorly-studied family of bismuthates. This observation opens up new perspectives for a deeper understanding of the phenomenon of high-temperature superconductivity, a topic which is at the core of condensed matter research since more than 30 years. The paper by Nicoletti et al has been published in the PNAS.
Since the beginning of the 20th century, superconductivity had been observed in some metals at temperatures only a few degrees above the absolute zero (minus...
16.08.2017 | Event News
04.08.2017 | Event News
26.07.2017 | Event News
18.08.2017 | Life Sciences
18.08.2017 | Physics and Astronomy
18.08.2017 | Materials Sciences