Richard A. O'Connor Discusses CD4+T Helper Cells
Fast Moving Front Commentary, September 2010
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Article: Translational Mini-Review Series on Th17 Cells: CD4+T helper cells: functional plasticity and differential sensitivity to regulatory T cell-mediated regulation
Authors: O'Connor, RA;Taams, LS;Anderton,
SM |
Richard A. O'Connor talks with ScienceWatch.com and answers a few questions about this month's Fast Moving Fronts paper in the field of Immunology.
Why do you think your paper is highly
cited?
In recent years the number of recognized T cell subsets has expanded to include both regulatory T cells (Treg), which help to maintain peripheral tolerance, and Th17 cells, which are important drivers of autoimmune pathology. These discoveries have energized research in T cell biology.
Characterization of the roles of Treg and Th17 in basic models of inflammation has provided new targets for immune based therapies while study of the developmental relationship between Treg and Th17 has revealed hitherto unsuspected levels of functional plasticity in both effector and regulatory T cell subsets.
Our paper appeared in a Translational Mini-Review Series on Th17 cells and brought together studies addressing the comparative susceptibility of effector T cell subsets to Treg-mediated suppression and the functional plasticity of regulatory T cells.
Does it describe a new discovery, methodology, or
synthesis of knowledge?
"The T cells driving inflammation in asthma and allergy for example do so via different mechanisms to those driving inflammation in models of multiple sclerosis."
Our review collates data regarding the ability of Treg to suppress divergent subsets of effector T cells. Regulatory T cells expressing the transcription factor Foxp3 are central players in preventing the over-amplification of inflammatory responses and in particular responses against self-antigens.
Many models of immune-mediated pathology are driven by highly polarized T cells responses, for example, Th-2 responses drive inflammation in models of allergy and asthma while Th1 and/or Th17 responses predominate in models such as collagen-induced arthritis and experimental allergic encephalomyelitis (EAE).
Whether or not Treg can regulate differentially polarized responses with equal efficiency and whether any sympathetic tuning exists between the character of the autoaggressive T cell responsible for driving inflammation and that of the Treg promoting its resolution are ideas we have explored.
Would you summarize the significance of your paper
in layman's terms?
CD4+ T cells which react to components of the body's own tissues, can drive inflammatory responses, resulting in tissue damage. It is essential that the activation of these potentially dangerous cells is tightly restricted to prevent the development of autoimmune-pathology.
A subpopulation of CD4+ T cells known as regulatory T cells (Treg for short,) are charged with limiting the activation of autoaggressive T cells. Without functional Treg the unrestrained activity of auto-reactive T cells leads to devastating pathology in both mice and men.
Consequently there is much interest in the potential of Treg to provide novel cell-based therapies for application in autoimmune conditions such as Type 1 diabetes and multiple sclerosis. A great deal of research effort has gone into characterizing the CD4+ T cells driving auto-immune pathology and it appears that different conditions are associated with T cells producing different patterns of pro-inflammatory mediators.
The T cells driving inflammation in asthma and allergy, for example, do so via different mechanisms to those driving inflammation in models of multiple sclerosis. Whether or not Treg are equally well able to suppress the activation of these different types of effector T cells is an important topic for consideration in developing Treg based therapies and provides the topic of our review.
How did you become involved in this research, and
how would you describe the particular challenges, setbacks, and
successes that you've encountered along the way?
The Anderton lab has been involved in researching the role of regulatory T cells in experimental autoimmune encephalomyelitis (the mouse model of the human condition multiple sclerosis) for several years. Mandy McGeachy was the first to identify an accumulation of Treg in the central nervous system (CNS) associated with the resolution of disease.
We subsequently became interested in how Treg might modulate the activity of effector T cells in the CNS and took advantage of mice expressing a Treg-specific GFP reporter to allow us to isolate these cells and assay their function. We found that while Treg were highly effective in suppressing the production of the Th1-associated cytokine IFN-gamma by CNS-effector cells, they were unable to suppress production of the IL-17 by CNS-derived Th17 cells.
This was the first observation suggesting to us that there may be a
hierarchy of susceptibility to Treg-mediated suppression of effector T cell
function. Similar findings were emerging in other models of autoimmunity,
and with burgeoning interest in the plasticity of effector and regulatory T
cells, we thought it timely to offer a review of the literature to
date.
Richard A. O'Connor
University of Edinburgh
Centre for Inflammation Research
Centre for Multiple Sclerosis Research
Queen's Medical Research Institute
Edinburgh, UK
KEYWORDS: EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; GROWTH-FACTOR-BETA; CENTRAL-NERVOUS-SYSTEM; ROR-GAMMA-T; ARYL-HYDROCARBON RECEPTOR; TRANSCRIPTION FACTOR FOXP3; SCURFY SF MOUSE; TGF-BETA; CUTTING EDGE; DENDRITIC CELLS.