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The Environment and T-Cell Differentiation

By Robin Arnette
February 2010

Dan Littman, M.D., Ph.D.
Littman is currently the Helen L. and Martin S. Kimmel Professor of Molecular Immunology in the Departments of Pathology and Microbiology at the Skirball Institute Program of Molecular Pathogenesis at the New York University School of Medicine. (Photo courtesy of Steve McCaw)

Anton Jetten, Ph.D.
Co-host Anton Jetten, above, "is the only other person in the world who has the interest in RORgamma that we do," Littman joked. (Photo courtesy of Steve McCaw)

Donald Cook, Ph.D.
Co-host Don Cook shares Littman's interests in T-cell differentiation, especially as it relates to the lung's immune responses to aeroallergens. (Photo courtesy of Steve McCaw)

Jau-Shyong Hong, Ph.D.
With his interests in inflammation-related neurodegeneration of dopamine neurons, NIEHS Neuropharmacology Group Principal Investigator Jau-Shyong Hong, Ph.D., found much of interest in Littman's analysis of immune response signaling. (Photo courtesy of Steve McCaw)

Yukimasa Takeda, Ph.D.
NIEHS Visiting Fellow Yukimasa Takeda, Ph.D., above, is a member of Jetten's Cell Biology Group. (Photo courtesy of Steve McCaw)

Xiaoling Li, Ph.D., left, and Postdoctoral Fellow Xiumei Guo, Ph.D.
Sitting with graduate students visiting from Duke University are NIEHS Principal Investigator Xiaoling Li, Ph.D., left, and Postdoctoral Fellow Xiumei Guo, Ph.D., of the Mammalian Aging Group. (Photo courtesy of
Steve McCaw)

The Distinguished Lecturer for the month of January, Dan Littman, M.D., Ph.D., explained the contributions of several factors involved in the maturation of thymus-derived lymphocytes, also known as T-lymphocytes or T-cells, in a seminar titled "Role of Environmental and Intrinsic Factors in the Differentiation of Inflammatory T-cells." Laboratory of Respiratory Biology investigators Anton Jetten, Ph.D., and Donald Cook, Ph.D., co-hosted the January 19 lecture.

Work by Littman on viral pathogenesis and T-cells has led to several major discoveries in immunology, but his presentation to the NIEHS community focused on the environmental factors that affect T-cell development.

Nuclear transcription factors in T-cell regulation and development

During Littman's research career, he devoted much of his efforts to understanding the involvement of ROR gamma t (RORγt) in T-cell lineage specification, particularly the differentiation of Th17 cells, a group of T-helper cells that have several functions. Although the main job of Th17 cells is to kill extracellular pathogens at mucosal barriers, they are also thought to be involved in tissue repair and, most importantly, associated with human autoimmune diseases and a variety of mouse inflammatory models. He said that he and his group accidently found the connection between RORγt and Th17 cells five years ago, but the timing was perfect since Th17 research was just beginning to heat up.

"Th17 cells make the cytokines [cellular signaling molecules] interleukin-17 (IL-17), IL-17F and IL-22 and become differentiated in the presence of IL-6 and transforming growth factor beta (TGF-β)," Littman explained. "However, work with one of our collaborators showed that rodent cells that lacked the nuclear receptor RORγt produced no IL-17, whereas cells with RORγt had an abundance of IL-17. Since onlyTh17 cells make IL-17, we knew there was a connection."

AhR and the immune system

According to Littman, although aryl hydrocarbon receptor (AhR) is not a nuclear receptor, it is still a ligand-regulated transcription factor. It is responsive to both natural and man-made environmental toxins such as dioxin. Other labs had reported that AhR had a role in Th17 differentiation, and Littman's unpublished data suggested that when T-helper cells were differentiated to the Th17 lineage in vitro, AhR was also induced. AhR's induction level was similar to the induction of RORγt.

"Since some of our previous studies had demonstrated that the immune response gene forkhead box P3 (Foxp3) inhibited RORγt by binding to it," Littman argued, "we believe that AhR is required for induction of IL-22 and for clearance of potentially lethal intestinal pathogenic bacteria."

Some microbes fight off other bacterial infections

Littman said IL-22 drove the production of antimicrobial peptides that regulated the homeostasis of intestinal microflora, so his group became interested in studying the possible involvement of bacteria in Th17 cell differentiation.

When he treated recently-weaned mice with antibiotics, their intestinal Th17 cell count decreased. However, placing these mice in a cage with feces from mice that had not been treated caused their Th17 cell number to increase - showing there were differences in Th17 cell numbers according to the source of the mice.

"The mice purchased from Taconic Farms had lots of Th17 cells, but the same strain from Jackson Labs had very few," he said. A hybridization-based screen for DNA of all known bacteria determined that the Taconic Farms mice had Segmented filamentous bacteria (SFB) in their intestine, and further analysis determined that these mice also had increased amyloid A proteins in their intestine and high levels of IL-22 and IL-17 in their intestinal T-cells.

Littman concluded, "If you infect mice colonized with SFB with Clostridium difficile (C. difficile) an important hospital-acquired pathogen, we propose that the SFB would produce a signal through the amyloid A proteins, which would lead to the production of Th17 cells and eventually the making of IL-17 and IL-22. These two cytokines would release the antimicrobial peptides that would keep C. difficile in check."

Littman's goal is to find out if scientists can use bacteria or modulate RORγt activity to move the immune system away from susceptibility to infection and inflammatory processes.

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