Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Insights into the immune system, from the fates of individual T cells

21.03.2013
Findings could enable better modeling and manipulation of immune response

By charting the differing fates of individual T cells, researchers have shown that previously unpredictable aspects of the adaptive immune response can be effectively modeled.


An immune response derived from a single T cell can be visualized directly ex vivo: Progeny of a specific single CD8 T cell is characterized by simultaneous expression of CD8 (x axis) and a defined heritable marker (y axis) setting it apart from all endogenous cells. Here every pixel stands for a cell. A color-coded heatmap indicates high (blue) and low cell density (red). The picture displays more than 20,000,000 cells, only a tiny fraction of which (within the black box) are derived from single transferred T cells.

Credit: Photo by Uli Benz, copyright TU Muenchen.

The crucial question: What determines which of the immune system's millions of cells will mobilize to fight an acute infection and which will be held back to survive long-term, forming the basis of the immunological memory? The scientists' findings, published in the journal Science, could have implications for improved immunotherapy and vaccination strategies.

The scientists found that the immediate immune response to an infection or tumor is mounted by a relatively tiny fraction of the so-called CD8+ T cells that are capable of recognizing the associated antigen. These few rapidly expand into giant populations of short-lived T cells targeted at killing infected cells or cancer cells. Meanwhile the vast majority remain in smaller populations geared toward longevity, to help ensure that the immune system will remember the antigen when it appears again in the future.

"Up to now, it was only possible to observe groups of immune cells during the response to an infection," says Prof. Dirk Busch of the Technische Universitaet Muenchen (TUM). "We have developed technology that enables us to observe individual T cells." Together with innovative cell processing technology, the researchers brought theoretical systems biology and clinical expertise to bear on this investigation, a collaboration of TUM, the University of Heidelberg, the Helmholtz Center Munich, the German Cancer Research Center (DKFZ), and the National Center for Infection Research (DZIF).

Marking the threshold of predictability

A single T cell is theoretically capable of generating an adaptive immune response by developing into diverse and expanding populations, fighting the acute infection as well as providing lasting memory for the future. But a fundamental question – whether an effective response is predetermined on the level of an individual T cell or emerges from the commingled fates of multiple cells – had never been put to the test. Another unresolved question concerned the order in which populations of short-lived killer cells and long-lived memory cells develop.

To address these questions, researchers at TUM began by introducing specially marked T cells into mice and then triggering a specific immune reaction. Around seven days later, they were able to determine how many descendant cells, and what kinds, had been generated by individual T cells. Biomathematical modeling, using an approach co-developed with the group of Prof. Thomas Hoefer at Heidelberg, helped to explain what the data showed. "One can't predict which 'career paths' the descendants of an individual killer T cell will take, " says first author Veit Buchholz, a medical resident at TUM. "This is a matter of chance, like a single roll of the dice. To generate a predictable immune response, we have found that a sample of at least 50 individual cells is needed."

From analysis of many of the huge populations of short-lived killer cells and the relatively tiny populations of long-lived memory cells, the researchers were able to reconstruct the T cells' development program and predict their behavior: All of the cells proceed along the same path of development, but they don't go the same distance. That is, the few cells that generate giant populations of short-lived infection fighters have gone through the same stage as those fated to produce memory cells – but they have left that stage behind to provide immediate protection.

Beyond the results themselves, another important outcome of this study is increased confidence in the combined power of the in vivo and in silico approaches. "The fact that the experimental results confirmed our predictions in detail has strongly supported our theory," says Prof. Hoefer, leader of the Heidelberg group.

There are several ways these findings could become important in the setting of human health, the researchers explain – in improving the effectiveness of immunotherapy against cancer, for example, or in optimizing treatment for older people, who tend to have significantly fewer copies of a given type of immune cell. "The future memory cell stands at the beginning of an expansion process with two extreme forms of differentiation," Buchholz says, "and ideally there should be a balance, so that the memory pool is not depleted. So we can think about how to tweak vaccination schemes to first allow expansion and not let differentiation kick in too early."

This research was supported by the German Research Foundation (DFG) through SFB TR36 (TP-B10/13, TP-Z1), SFB 1054 (TP-B09), and SFB 914 (TP-B04); the Federal Ministry of Education and Research (BMBF) ForSysPartner (no. 0315267E); the TUM Institute for Advanced Study; the European Research Council through EU-FP7 SYBILLA (no. 201106); the Initiative and Networking Fund of the Helmholtz Association within the Helmholtz Alliance on Immunotherapy of Cancer; and the National Science Foundation under grant no. NSF PHY11-25915.

Publication:

Disparate individual fates compose robust CD8+ T cell immunity

Veit R. Buchholz, Michael Flossdorf, Inge Hensel, Lorenz Kretschmer, Bianca Weissbrich, Patricia Graef, Admar Verschoor, Matthias Schiemann, Thomas Hoefer, and Dirk H. Busch.

Science 2013, DOI: 10.1126-science.1235454
Contact:
Prof. Dirk Busch
Institute for Medical Microbiology, Immunology, and Hygiene
Technische Universitaet Muenchen
Tel.: +49 (0)89 4140-4120
E-mail: dirk.busch@mikrobio.med.tum.de http://www.mikrobio.med.tu-muenchen.de
Technische Universitaet Muenchen (TUM) is one of Europe's leading universities. It has roughly 500 professors, 9,000 academic and non-academic staff, and 32,000 students. It focuses on the engineering sciences, natural sciences, life sciences, medicine, and economic sciences. After winning numerous awards, it was selected as an "Excellence University" in 2006 and 2012 by the Science Council (Wissenschaftsrat) and the German Research Foundation (DFG). In both international and national rankings, TUM is rated as one of Germany's top universities and is dedicated to the ideal of a top-level research-oriented entrepreneurial university. The university's global presence includes offices in Beijing (China), Brussels (Belgium), Cairo (Egypt), Mumbai (India) and São Paulo (Brazil). The German Institute of Science and Technology (GIST - TUM Asia), founded in 2002 in Singapore, is the first research campus of a German university abroad.

Patrick Regan | EurekAlert!
Further information:
http://www.tum.de

More articles from Life Sciences:

nachricht Symbiotic bacteria: from hitchhiker to beetle bodyguard
28.04.2017 | Johannes Gutenberg-Universität Mainz

nachricht Nose2Brain – Better Therapy for Multiple Sclerosis
28.04.2017 | Fraunhofer-Institut für Grenzflächen- und Bioverfahrenstechnik IGB

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Making lightweight construction suitable for series production

More and more automobile companies are focusing on body parts made of carbon fiber reinforced plastics (CFRP). However, manufacturing and repair costs must be further reduced in order to make CFRP more economical in use. Together with the Volkswagen AG and five other partners in the project HolQueSt 3D, the Laser Zentrum Hannover e.V. (LZH) has developed laser processes for the automatic trimming, drilling and repair of three-dimensional components.

Automated manufacturing processes are the basis for ultimately establishing the series production of CFRP components. In the project HolQueSt 3D, the LZH has...

Im Focus: Wonder material? Novel nanotube structure strengthens thin films for flexible electronics

Reflecting the structure of composites found in nature and the ancient world, researchers at the University of Illinois at Urbana-Champaign have synthesized thin carbon nanotube (CNT) textiles that exhibit both high electrical conductivity and a level of toughness that is about fifty times higher than copper films, currently used in electronics.

"The structural robustness of thin metal films has significant importance for the reliable operation of smart skin and flexible electronics including...

Im Focus: Deep inside Galaxy M87

The nearby, giant radio galaxy M87 hosts a supermassive black hole (BH) and is well-known for its bright jet dominating the spectrum over ten orders of magnitude in frequency. Due to its proximity, jet prominence, and the large black hole mass, M87 is the best laboratory for investigating the formation, acceleration, and collimation of relativistic jets. A research team led by Silke Britzen from the Max Planck Institute for Radio Astronomy in Bonn, Germany, has found strong indication for turbulent processes connecting the accretion disk and the jet of that galaxy providing insights into the longstanding problem of the origin of astrophysical jets.

Supermassive black holes form some of the most enigmatic phenomena in astrophysics. Their enormous energy output is supposed to be generated by the...

Im Focus: A Quantum Low Pass for Photons

Physicists in Garching observe novel quantum effect that limits the number of emitted photons.

The probability to find a certain number of photons inside a laser pulse usually corresponds to a classical distribution of independent events, the so-called...

Im Focus: Microprocessors based on a layer of just three atoms

Microprocessors based on atomically thin materials hold the promise of the evolution of traditional processors as well as new applications in the field of flexible electronics. Now, a TU Wien research team led by Thomas Müller has made a breakthrough in this field as part of an ongoing research project.

Two-dimensional materials, or 2D materials for short, are extremely versatile, although – or often more precisely because – they are made up of just one or a...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Fighting drug resistant tuberculosis – InfectoGnostics meets MYCO-NET² partners in Peru

28.04.2017 | Event News

Expert meeting “Health Business Connect” will connect international medical technology companies

20.04.2017 | Event News

Wenn der Computer das Gehirn austrickst

18.04.2017 | Event News

 
Latest News

Wireless power can drive tiny electronic devices in the GI tract

28.04.2017 | Medical Engineering

Ice cave in Transylvania yields window into region's past

28.04.2017 | Earth Sciences

Nose2Brain – Better Therapy for Multiple Sclerosis

28.04.2017 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>