T lymphocyte biology
Past. The lab succeeded in T cell cloning, T cell receptor (TCR) gene transfer and thereby establishing the abTCR as a molecule essential and sufficient for MHC-restricted antigen recognition. This permitted construction of TCR transgenic mice, in which the principles of positive and negative selection (rescue from and induction of programmed cell death) of developing T cells were discovered. These receptor-controlled developmental checkpoints enable the immune system to adapt to "self " and match lineage commitment and receptor specificity. TCR transgenic mice were likewise essential in the discovery of the pre-TCR that has an essential role in TCRb allelic exclusion and generation of the diverse TCR repertoire.
Presently, we make use of T cell receptor transgenic mice to define mechanisms of extra- and intra-thymic generation of antigen-specific regulatory T cells and study their role in murine models of autoimmunity and cancer. The knowledge obtained in TCR transgenic mice is validated in wild-type mice with the goal to specifically prevent unwanted immune reactions.
With regard to the role of the pre-T cell receptor in differentiation of ab T cells and thymic lymphoma, we analyze the synergy of TCR and Notch signaling in lineage fate determination and malignant transformation.
Concerning the contribution of extrathymic precursors to the development of T cells, we have identified T and B-committed as well as T-committed extrathymic precursors and are in the process of studying their contribution to the regeneration of the T cell lineage.
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Papers & Publications:
Marson, A.*, Kretschmer, K.*, Frampton, G.M., Jacobsen, E.S., Polansky, J., MacIsaac, K.D., Levine, S.S, Fraenkel, E., von Boehmer, H., Young, R.A. Foxp3 occupancy and regulation of key target genes during T-cell stimulation. Nature 445, 931-5 (2007).
Krueger, A. and von Boehmer, H. Identification of a T lineage committed progenitor in adult blood. Immunity 26, 105-116 (2007).
Garbe, A.I., Krueger, A., Gounari, F., Zuniga-Pflucker, J.C. and von Boehmer, H. Differential synergy of Notch and T cell receptor signaling determines αβ versus γδ lineage fate. J. Exp. Med. 203, 1579-90 (2006).
Kretschmer, K., Apostolou, I., Hawiger, D., Khazaie, K., Nussenzweig, M.C. and von Boehmer, H. Inducing and expanding regulatory T cells by foreign antigen. Nat. Immunol. 6, 1219-1227 (2005).
von Boehmer, H. Lymphocyte survival and lineage determination through positive selection. In “Great Experiments in Biology.” Ed. B. Lewin.<http://www.ergito.com/lookup.jsp?expt=vonboehmer> (2001).
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