Karsten Kretschmer

Cellular and molecular pathways of antigen-specific immunosuppression

Previous and current research

CD4+CD25+ regulatory T cells (Treg) expressing the forkhead family transcription factor Foxp3 play an essential role in the regulation of immune responses in mice and humans. There is emerging consensus that Treg represent a suitable tool to induce antigen-specific immunological tolerance in the fully mature immune system. We have addressed the possibility that Treg can be exploited to prevent or even reverse ongoing autoimmunity or transplant rejection by developing methods that permit the manipulation of Treg numbers and function in vivo. We reported recently on the de novo generation of antigen-specific Foxp3+CD4+CD25+ Treg in vivo by targeting peptides to DCs via recombinant DEC-205 antibodies. Having established a reproducible protocol that efficiently generates Foxp3+CD25+ Treg with potent in vivo suppressive capacity, we now focus on assessing whether DEC-205-mediated targeting in mouse models of autoimmune disease and transplantation tolerance provides an alternative to treatments that currently involve general immunosuppression.

The important role of Foxp3 as a key mediator of Treg development and function prompted us to investigate molecular targets of this transcription factor by genome-wide DNA based location analysis (ChIP-on-Chip) in conjunction with global gene expression profiling. Remarkably, the predominant effect of Foxp3 binding is to suppress the NFAT-dependent transcriptional activation of target genes upon T cell receptor stimulation. Many of the direct Foxp3 target genes have previously been implicated in autoimmune diseases, suggesting that therapeutic strategies to recapitulate the function of Foxp3 may have clinical utility. Therefore, we are currently focussing on the molecular pathways controlling Foxp3 expression and the mechanisms involved in the transcriptional program specified by Foxp3 in thymic and extrathymic Treg generation.

Future prospects and goals

• developing new approaches to prevent or silence unwanted immunity by de novo generation or expansion of antigen-specific Treg in vivo
• understanding the molecular mechanisms governing the development and function of Treg with particular interest in the role of Foxp3 in establishing and maintaining a suppressor phenotype

The above studies employ experimental techniques including traditional biochemical and molecular biological analysis, global gene expression profiling and ChIP-on-Chip analysis; bioinformatics; genetic approaches including conditional gene targeting and inducible transgenesis; cellular immunological analysis utilizing both in vitro and in vivo techniques; and autoimmune mouse models.

About

Selected publications

A. Marson*, K. Kretschmer*, G.M. Frampton, E.S. Jacobsen, J.K. Polansky, K.D. MacIsaac, S.S. Levine, E. Fraenkel, H. von Boehmer, and R.A. Young (2007): Foxp3 occupancy and regulation of key target genes during T-cell stimulation. Nature, 445(7130):931-935. *These authors contributed equally.

K. Kretschmer, T.S.P. Heng, and H. von Boehmer (2006): De novo production of antigen-specific suppressor cells in vivo. Nature Protocols, 1(2): 653-661.

K. Kretschmer, I. Apostolou, E. Jaeckel, K. Khazaie, and H. von Boehmer (2006): Making regulatory T cells with defined antigen specificity: Role in autoimmunity and cancer. Immunological Reviews, 212: 163-169.

I. Apostolou, K. Kretschmer, and H. von Boehmer (2006): Peptide-based instruction of suppressor commitment in naïve T cells. The Autoimmune Diseases, 133-138.  

E. Jaeckel, K. Kretschmer, I. Apostolou, and H. von Boehmer (2006): Instruction of Treg commitment in peripheral T cells is suited to reverse autoimmunity. Seminars in Immunology, 18(2): 89-92.

K. Kretschmer, I. Apostolou, D. Hawiger, K. Khazaie, M.C. Nussenzweig, and H. von Boehmer (2005): Inducing and expanding regulatory T cells by foreign antigen. Nature Immunology, 6: 1219-1227.

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