Environmental Factor, July 2011, National Institute of Environmental Health Sciences
T cells take center stage at NIEHS symposium
By Ernie Hood
Cook, who organized the meeting, welcomed attendees to the symposium and presented his group's work on the immunology of allergic asthma. (Photo courtesy of Steve McCaw)
Cook said of keynote speakers Trinchieri, above, and Paul, "It was an honor to have immunologists of their stature at the meeting. In addition to their outstanding presentations, they asked questions of the other speakers and interacted well with the meeting attendees." (Photo courtesy of Steve McCaw)
Paul gave his talk an amusing and evocative title, "Cytokines and CD4 T cells: Dance partners at the immunology ball." His work with Interleukin 1 may lead to new strategies to prevent and treat viral and bacterial infections, especially through the development of next-generation vaccines to manipulate immune response. (Photo courtesy of William Paul)
Gunn was the only NIEHS grantee (https://tools.niehs.nih.gov/portfolio/index.cfm?action=portfolio.grantdetail&grant_number=U01ES017219) speaking at the symposium. With his counter-terrorism funding, he studies the prevention of inflammatory lung injury after chlorine exposure. (Photo courtesy of Steve McCaw)
NIEHS played host to a diverse group of some 100 scientists from the field of immunology June 9, with a daylong workshop titled "Emerging Concepts in T Cell Activation and Disease." The symposium, which was attended by more than 100 researchers, was organized by Donald Cook, Ph.D.(https://www.niehs.nih.gov/research/atniehs/labs/lrb/immuno-gen/index.cfm), principal investigator and head of the NIEHS Immunogenetics Group within the Laboratory of Respiratory Biology.
Public health and treatment implications
The meeting was an opportunity for scientists in the Research Triangle, N.C. area to hear from both local and international experts in the field and learn more about the mechanisms of T cell activation, the workhorses of the adaptive immune system. Under normal circumstances they help ward off infections, but all too often the delicately balanced immune system runs awry.
T cells are a component in almost all diseases, and have a substantial role in causing the pathology seen in many major chronic conditions, such as allergic asthma, diabetes, and arthritis. Modulating T cell response is an area rich in therapeutic potential, but, as Cook said, "To be able to do that effectively, it's going to be important to learn more about how T cells are activated, so that we can either raise the responses or lower them, depending on what we need to do for particular diseases."
The meeting also served to promote collaboration among T cell biologists in the Triangle area, by allowing local investigators with common interests to interact and learn more about each other's work. To that end, several scientists from Duke University and the University of North Carolina made presentations about their research programs and results. (see text box)
Showcasing authorities in T cell research
The symposium also attracted two of the leading lights of the field - Giorgio Trinchieri, M.D.(https://ccr.cancer.gov/Cancer-and-Inflammation-Program/giorgio-trinchieri) , chief of the Laboratory of Experimental Immunology within the Center for Cancer Research at the National Cancer Institute, and William Paul, M.D.(https://www.niaid.nih.gov/labsandresources/labs/aboutlabs/li/generalimmunologysection/pages/paul.aspx) , chief of the Laboratory of Immunology at the National Institute of Allergy and Infectious Diseases. Both spoke about investigations into T cell activation and disease.
Trinchieri's research focuses on the interplay between inflammation and innate resistance and adaptive immunity, and the role of pro-inflammatory cytokines in the regulation of hematopoiesis, innate resistance, and immunity. He discovered interleukin-12 while at the Wistar Institute in 1989 and, for many years, has been characterizing the molecular mechanisms of interleukin-12 production and its role in tumor immunity, infections, and autoimmunity.
Paul's talk described the emerging knowledge about the fates and functions of CD4 T helper (Th) cells and the various cytokines produced by some of the major Th cell sub-types, particularly many forms of interleukins. Depending on the stimulus involved, such as a specific antigen, so-called naïve T cells differentiate into many subtypes through highly complex signaling processes. They perform a variety of functions in the immune response, and it is now emerging that they exhibit plasticity as well, further complicating an already complex picture.
T cell studies at NIEHS
Cook also had the opportunity to describe his group's work on the immunology of allergic asthma, which has identified a specific cell type, called a CD103+ dendritic cell, required for the initiation of allergic responses to inhaled allergens. The dendritic cell acquires inhaled allergens in the lung and presents them to naïve T cells in a way that promotes Th2 responses that are typically associated with allergic diseases. Therapies that inhibit CD103+ dendritic cell function could eventually be used to prevent or treat allergic asthma, Cook explained.
A common theme in the presentations was the growing awareness that immune responses are both more complex and more flexible than previously thought. As Cook explained, "Many molecules that have been traditionally thought to function in restricted T cell subsets actually function in multiple subsets of T cells and modulate the behavior of those subsets in unexpected ways. For example, specific transcription factors, which control the expression of genes, are involved in more types of responses than has been appreciated until now."
(Ernie Hood is a contract writer with the NIEHS Office of Communications and Public Liaison.)
Suited to a T
Each of the speakers at the T cell activation symposium presented new, exciting work in the field.
- Michael Dee Gunn, M.D., Duke University, CCR-2-dependent and CCR-7-dependent DC populations differentially regulate T cell immune response: Gunn described studies of inflammatory cell migration within various forms of immune response. It appears that tissues imprint local dendritic cells to mount a characteristic immune response for that tissue, while cases of severe insult stimulate recruitment of CCR2-dependent monocyte-derived dendritic cells, in a robust Th1 immune response.
- Roland Tisch, Ph.D., University of North Carolina, T cell co-receptor blockade and the re-establishment of self tolerance: Tisch has found that blockade of molecules on T cells known as CD4 and CD8 induces rapid reversal of diabetes in mice without affecting their immune responses to foreign antigens. The success of this approach suggests it might be effective for the treatment of other T cell-mediated autoimmune diseases such as multiple sclerosis and rheumatoid arthritis.
- Mari Shinohara, Ph.D., Duke University, Novel intracellular isoform of osteopontin (iOPN) in antigen-presenting cells: Although the secreted form of the molecule osteopontin (OPN) is known to promote inflammation and immunity against microbial infections, Shinohara has found that intracellular OPN (iOPN) controls excessive TNF production by macrophages through simultaneous stimulation of CD40 and strong PRR signaling pathways. Her study has elucidated how OPN switches its pro-inflammatory role to an anti-inflammatory in the presence of adaptive immune cells that supply CD40L under acute infections.
- Qi-Jing Li, Ph.D., Duke University, Harnessing microRNAs to micromanage T cell immunity: Li described his group's work on characterizing the role of non-coding RNAs (ncRNAs), specifically microRNAs (miRNAs), a novel class of small ncRNAs that mediate post-transcriptional gene silencing, in immune response. He focused particularly on the role of a specific cluster of miRNAs, miR-17-92, which among other functions comprehensively supports the CD4 T cell response during antigen challenge.
- Yisong Wan, Ph.D., University of North Carolina, Regulation of Treg function and Foxp3 expression - Wan's group has shown that GATA3, a transcription factor known for its role in Th2 differentiation, is also an important molecule for regulatory T cell (Treg) function. GATA 3 appears to function in Treg cells in part through controlling the expression of a molecule known as Foxp3.
- Weiguo Zhang, Ph.D., Duke University, Transmembrane adaptor proteins in T cell activation and autoimmunity: Zhang has described how two transmembrane adaptor proteins, LAT and LAB, control T cell activation and autoimmunity. He recently showed that LAT is particularly important in the development and function of Treg cells and control of T cell expansion and cytokine production.
- Lishan Su, Ph.D., University of North Carolina, Sanity of host immunity: Foxp3+Treg cells in HIV-1 replication and pathogenesis: Su has developed mice with humanized immune systems, which allows him to use the animals to investigate the roles of Tregs in HIV infection. He showed that although HIV suppresses anti-virus immunity during the early stages of the infection, Tregs suppress HIV-induced immune hyperactivation during the later stages of disease, and thereby slow down disease progression.