[GRG] transfer of single cell-derived immunocompetence reveals stemness of CD8+ central memory T cells

http://ift.tt/1hG1Obo
releases/short/article/31707/

A fundamental finding with implications for clinical cell therapy

Experiments prove “stemness” of individual immune memory cells

Prof. Dirk Busch, Patricia Gräf and Veit Buchholz (Photo: Astrid
Eckert / TUM)

Prof. Dirk Busch, Patricia Gräf and Veit Buchholz (Photo: Astrid
Eckert / TUM)

24.07.2014, Research news

Researchers in Germany and the U.S. have proven for the first time
that specific individual cells of the immune system, termed central
memory T cells, have all the essential characteristics of adult
tissue stem cells. Such cells are capable of perpetuating
themselves indefinitely as well as generating diverse offspring
that can reconstitute “tissue” function. These findings indicate
that it should be possible to fully restore specific immunity to
pathogens in patients with a compromised immune system by
substitution of small numbers of central memory T cells. The
results, published in the journal Immunity, highlight the
therapeutic promise of “stemness” in T cells.

The immune system has evolved to recognize and respond to threats
to health, and to provide life-long memory that prevents recurrent
disease. A detailed understanding of the mechanism underlying
immunologic memory, however, has remained elusive. Since 2001,
various lines of research have converged to support the hypothesis
that the persistence of immune memory arises from a reservoir of
immune cells with stem-cell-like potential. Until now, there was no
conclusive evidence, largely because experiments could only be
carried out on populations of cells. This first strict test of the
stem cell hypothesis of immune memory was based on mapping the
fates of individual T cells and their descendants over several
generations.

That experimental capability was developed through a long-term
collaboration, focused on clinical cell processing and
purification, between researchers based in Munich and Seattle.
Since 2009, the groups of Prof. Dirk Busch at the Technische
Universität München (TUM) and Prof. Stanley Riddell at the Fred
Hutchinson Cancer Research Center have combined their technological
and clinical expertise under the auspices of the TUM Institute for
Advanced Study. The University of Heidelberg, the University of
Düsseldorf, the Helmholtz Center Munich, the German Cancer Research
Center (DKFZ), and the National Center for Infection Research
(DZIF) also contributed to the present study.

Homing in on the “stemness” of T cells

After generating an immune response in laboratory animals, TUM
researchers Patricia Graef and Veit Buchholz separated complex
“killer” T cell populations enlisted to fight the immediate or
recurring infection. Within these cell populations, they then
identified subgroups and proceeded with a series of single-cell
adoptive transfer experiments, in which the aftermath of immune
responses could be analyzed in detail. Here the ability to identify
and characterize the descendants of individual T cells through
several generations was crucial.

The researchers first established that a high potential for
expansion and differentiation in a defined subpopulation, called
“central memory T cells,” does not depend exclusively on any
special source such as bone marrow, lymph nodes, or spleen. This
supported but did not yet prove the idea that certain central
memory T cells are, effectively, adult stem cells. Further
experiments, using and comparing both memory T cells and so-called
naive T cells – that is, mature immune cells that have not yet
encountered their antigen – enabled the scientists to home in on
stem-cell-like characteristics and eliminate other possible
explanations.

Step by step, the results strengthened the case that the
persistence of immune memory depends on the “stemness” of the
subpopulation of T cells termed central memory T cells: Individual
central memory T cells proved to be “multipotent,” meaning that
they can generate diverse types of offspring to fight an infection
and to remember the antagonist. Further, these individual T cells
self-renew into secondary memory T cells that are, again,
multipotent at the single-cell level. And finally, individual
descendants of secondary memory T cells are capable of fully
restoring the capacity for a normal immune response.

Insights with clinical potential

One implication is that future immune-based therapies for cancers
and other diseases might get effective results from adoptive
transfer of small numbers of individual T cells. “In principle, one
individual T cell can be enough to transfer effective and long-
lasting protective immunity for a defined pathogen or tumor antigen
to a patient,” says Prof. Dirk Busch, director of the Institute for
Medicial Microbiology, Immunology and Hygiene at TUM. “Isn’t that
astonishing?”

“These results are extremely exciting and come at a time when
immunotherapy is moving into the mainstream as a treatment for
cancer and other diseases,” says Prof. Stanley Riddell of the Fred
Hutchinson Cancer Research Center and the University of Washington.
“The results provide strong experimental support for the concept
that the efficacy and durability of T cell immunotherapy for
infections and cancer may be improved by utilizing specific T cell
subsets.”

This research was supported by the German Research Foundation (DFG)
through SFB TR36 (TP-B10/13) and SFB 1054 (TP-B09); by the
Initiative and Networking Fund of the Helmholtz Association within
the Helmholtz Alliance on Immunotherapy of Cancer; by the Federal
Ministry of Education and Research (BMBF) through the e:Bio program
(T-Sys); and by the U.S. National Science Foundation under Grant
No. NSF PHY11-25915.

Publication
“Serial transfer of single cell-derived immunocompetence reveals
stemness of CD8+ central memory T cells,” Patricia Graef, Veit R.
Buchholz, Christian Stemberger, Michael Flossdorf, Lynette Henkel,
Matthias Schiemann, Ingo Drexler, Thomas Höfer, Stanley R. Riddell,
and Dirk H. Busch. Immunity, Vol. 41, Issue 1, July 17, 2014.
DOI: 10.1016/j.immuni.2014.05.018

Contact
Prof. Dr. Dirk H. Busch
Institute for Medical Microbiology, Immunology and Hygiene
Technische Universität München
Tel: +49 89 4140 4120
dirk.busch@tum.de
http://ift.tt/1mHGRLb

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About Johnny Adams

My full-time commitment is to slow and ultimately reverse age related functional decline to increase healthy years of life. I’ve been active in this area since the 1970s, steadily building skills and accomplishments. I have a good basic understanding of the science of aging, and have many skills that complement those of scientists so they can focus on science to advance our shared mission. Broad experience Top skills: administration, management, information technology (data and programming), communications, writing, marketing, market research and analysis, public speaking, forging ethical win-win outcomes among stakeholders (i.e. high level "selling"). Knowledge in grant writing, fundraising, finance. Like most skilled professionals, I’m best described as a guy who defines an end point, then figures out how to get there. I enjoy the conception, design, execution and successful completion of a grand plan. Executive Director Gerontology Research Group (GRG). Manages Email discussion forum, web site, meetings and oversees supercentenarian (oldest humans, 110+ years) research. CEO / Executive Director Carl I. Bourhenne Medical Research Foundation (Aging Intervention Foundation), an IRS approved 501(c)(3) nonprofit. http://www.AgingIntervention.org Early contributor to Supercentenarian Research Foundation. Co-Founder Geroscience Healthspan Forum. Active contributor to numerous initiatives to increase healthy years of life. Co-authored book on conventional, practical methods available today to slow the processes of aging – nutrition, exercise, behavior modification and motivation, stress reduction, proper supplementation, damage caused by improper programs, risk reduction and others. Fundamental understanding of, and experience in the genomics of longevity (internship analyzing and curating longevity gene papers). Biological and technical includes information technology, software development and computer programming, bioinformatics and protein informatics, online education, training programs, regulatory, clinical trials software, medical devices (CAT scanners and related), hospital electrical equipment testing program. Interpersonal skills – good communication, honest, well liked, works well in teams or alone. Real world experience collaborating in interdisciplinary teams in fast paced organizations. Uses technology to advance our shared mission. Education: MBA 1985 University of Southern California -- Deans List, Albert Quon Community Service Award (for volunteering with the American Longevity Association and helping an elderly lady every other week), George S. May Scholarship, CA State Fellowship. BA psychology, psychobiology emphasis 1983 California State University Fullerton Physiological courses as well as core courses (developmental, abnormal etc). UCLA Psychobiology 1978, one brief but fast moving and fulfilling quarter. Main interest was the electrochemical basis of consciousness. Also seminars at the NeuroPsychiatric Institute. Other: Ongoing conferences, meetings and continuing education. Aging, computer software and information technology. Some molecular biology, biotech, bio and protein informatics, computer aided drug design, clinical medical devices, electronics, HIPAA, fundraising through the Assoc. of Fundraising Professionals. Previous careers include: Marketing Increasing skill set and successes in virtually all phases, with valuable experience in locating people and companies with the greatest need and interest in a product or service, and sitting across the table with decision makers and working out agreements favorable to all. Information Technology: Management, data analysis and programming in commercial and clinical trials systems, and bioinformatics and protein informatics. As IT Director at Newport Beach, CA based technology organization Success Family of Continuing Education Companies, provided online software solutions for insurance and financial professionals in small to Fortune 500 size companies. We were successful with lean team organization (the slower moving competition was unable to create similar software systems). Medical devices: At Omnimedical in Paramount CA developed and managed quality assurance dept. and training depts. for engineers, physicians and technicians. Designed hospital equipment testing program for hospital services division. In my early 20’s I was a musician, and studied psychology and music. Interned with the intention of becoming a music therapist. These experiences helped develop valuable skills used today to advance our shared mission of creating aging solutions.
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