Vijay K. Kuchroo talks with
ScienceWatch.com and answers a few questions about
this month's Fast Moving Fronts paper in the field of
Article: Reciprocal developmental pathways for the
generation of pathogenic effector T(H)17 and regulatory T
Authors: Bettelli, E;Carrier, YJ;Gao, WD;Korn, T;Strom,
TB;Oukka, M;Weiner, HL;Kuchroo, VK
Journal: NATURE, 441 (7090): 235-238, MAY 11 2006
Addresses: Brigham & Womens Hosp, Ctr Neurol Dis, 77 Ave
Louis Pasteur, Boston, MA 02115 USA.
Brigham & Womens Hosp, Ctr Neurol Dis, Boston, MA 02115
Harvard Univ, Sch Med, Beth Israel Hosp, Transplant Res Ctr,
Boston, MA 02115 USA.
Harvard Univ, Sch Med, Brigham & Womens Hosp, Ctr Neurol
Dis, Cambridge, MA 02139 USA. (addresses have been
Why do you think your paper is highly
This was one of the first papers which not only reported the identification
of differentiation factors for Th17 cells, but also showed that there is a
reciprocal relationship between inhibitory iTregs and proinflammatory Th17
Does it describe a new discovery, methodology, or
synthesis of knowledge?
It was a new discovery in terms of identifying the differentiation factors
for Th17 cells, a methodology to generate them, and it is also a synthesis
of knowledge, putting together the relationship between regulatory and
effector T cells.
Would you summarize the significance of your paper
in layman's terms?
Recently, a new group of T cells was identified which predominantly produce
a soluble factor called IL-17 and, therefore, the cells were named Th17
cells. These cells play an important role in clearing fungal and bacterial
infections but, more importantly, they induce tissue inflammation and
These cells have been implicated in inducing autoimmune diseases in humans
as well, including psoriasis, inflammatory bowel disease,
rheumatoid arthritis, and
multiple sclerosis. However, how
these cells are induced was not clear.
"We are in the process of developing a detailed map of
Our studies were the first to describe the factors which are required for
the generation of these cells—specifically, a soluble factor, IL-6,
produced during an infection or inflammation plays a key role in inducing
IL-6 plays a dual role, as first it suppresses the generation and functions
of protective/inhibitory Treg cells and induces the generation of highly
proinflammatory Th17 cells, thus providing a fertile ground for inducing
Our studies also showed that there is a reciprocal relationship between
proinflammatory Th17 and protective regulatory T cells and that IL-6 plays
a key role in regulating this balance.
How did you become involved in this research and
were any particular problems encountered along the way?
I became involved in this research soon after the discovery of Th17
cells—they are key cells instigating development of tissue
inflammation and autoimmunity. Our studies in the lab began with trying to
expand these cells in vitro so as to study their function.
At that time, IL-23 was described as the key cytokine responsible for
induction of these cells. However, when we activated naive T cells in
vitro with IL-23, we were not able to induce Th17 cells. After
repeating this experiment multiple times, we came to the conclusion that
other factors besides IL-23 must be differentiation factors for this T cell
Success came to us fortuitously! Mohammed Oukka in our lab had generated a
Fox-P3.GFP reporter mouse strain and, while characterizing the mouse
strain, he repeated the experiment, showing that the immunosuppressive
cytokine TGF-b induces Fox-P3 from naive T cells of the reporter mice.
In collaboration with Wenda Gao and Estelle Bettelli, Dr. Oukka
systematically added various cytokines to TGF-b to see their effect on the
induction of Fox-P3. Addition of IL-6 suppressed generation of Fox-P3+
Tregs and instead induced IL-17 producing Th17 cells. This led us to
hypothesize that there is a reciprocal relationship between Fox-P3+ Tregs
and IL-17 producing Th17 cells.
One of the major problems that we encountered was that we could not repeat
the observation that IL-23 is the differentiation factor for Th17 cells.
However, this also led us to identify the factors that lead to the
generation of Th17 cells.
Where do you see your research leading in the
We are in the process of developing a detailed map of Th17 development.
With this in mind, we should be able to identify nodal points and potential
drug targets that regulate the development of Th17 versus Treg cells.
Dr. Vijay K. Kuchroo
Samuel L. Wasserstrom Professor of Neurology
Harvard Medical School
Co-Director, Center for Infection and Immunology
Brigham Research Institute
Brigham and Women's Hospital
Boston, MA, USA Web