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Department of Immunology
Seminar Tuesday November 7, 2006, 16:00 hr, library 8th floor
"New concepts of regulatory T cell differentiation"
Carsten Schmidt-Weber
Swiss Institute of Allergy and Asthma Research, Davos, Switzerland
T cell differentiation is a key mechanism in immune regulation, which occurs prior clonal expansion
and thus determines the outcome of antigen-specific responses. Specific immune responses are
driven by antigen-specific T cells, which do not only expand after initial MHC-dependent antigen
contact, but do also polarize into effector cells.These differentiated cells are characterized by their
function and cytokine profile, such as IFN-g (Th1 cells), IL-4, -5, -13 (Th2 cells) and IL-17 (Th17). T
regulatory cells (Tregs) play an important role in the immune reaction, by maintaining tolerance,
whereas suppression against dangerous antigens leads to chronic infection or cancer. In contrast
underdeveloped suppression allows autoimmune or allergic reactions. It is unclear how Tregs are
induced and whether this induction occurs in shared pathways along with Th1 and Th2 differentiation.
As Th1 and Th2 cells, NFAT was found to be critically important to induce the FOXP3 gene. However
the induction of FOXP3 in naïve precursor T cells was potently inhibited by IL-4, whereas already
committed Tregs were resistant to counteraction by Th2 cytokines. Within the FOXP3 promoter we
identified a Treg – regulon in between the transcription start site and the NFAT/Ap-1 inducible region,
which keeps the NFAT/AP-1 mediated transactivation under control. Interestingly GATA-3 binds to this
region and inhibits FOXP3 transcription, both on reporter-gene level as well as on mRNA and protein
level. Furthermore we demonstrate that human T cells as well as animals engineered to constitutively
express GATA-3 in T cells are deficient in up-regulating FOXP3 in vitro and also show a decreased
number of CD25+ Tregs in the periphery. These results demonstrate that Th2-commitment overrides
and restrains development of regulatory T cells and now allows to integrate the Treg concept into the
paradigm of Th1/Th2 cell differentiation. Furthermore it indicates that Th2-driving conditions as they
occur in allergic inflammation are preventing the induction of regulatory T cells, forming the basis of
new adjuvants promoting tolerance induction.
Information: Rudi Hendriks, phone: 010-4087180, e-mail: [email protected]
Leonie Boven, phone:010-4087184, e-mail: [email protected]