Post Doctoral Fellow

Immune Disease Institute (Boston, MA)

In vivo visualization of thymocyte - APC interactions during intrathymic selection processes

The immune system protects the body from pathogens while being tolerant to self-antigens (Ag). To be able to distinguish between self and non-self, lymphocytes have to be educated.
T cell development takes place in the thymus. The thymus is composed of the outer cortex and the inner medulla. The cortex is mainly composed of cortical thymic epithelial cells (cTEC), macrophages (Mφ), CD4-CD8- double negative (DN) and CD4+CD8+ double positive (DP) thymocytes. In contrast to this, medullary thymic epithelial cells (mTEC), Mφ, dendritic cells (DC), CD4+CD8- single positive (CD4SP) and CD4-CD8+ single positive (CD8SP) thymocytes are the predominant cell types in the medulla. Interestingly, DCs as well as nerves and other vascular structures such as blood vessels and lymphatics, are enriched at the cortico-medullary junctions.
Common lymphoid progenitors (CLP) originated from the bone marrow (BM) enter the thymus at the cortico-medullary junctions. Upon entering, they migrate into the cortex where they randomly rearrange the β-chain of their T cell receptor (TCR). Consequently the β-chain is subjected to β-selection. Briefly, the β-chain associates with a pre-α-chain and forms a pre-TCR. Only if the pre-TCR supports signaling T cell development may progress to the next step.
After passing β-selection, the α-chain of the TCR will be randomly rearranged. The resulting TCR has to fulfill two requirements: It has to be self restricted but may not be autoreactive. To address the first point, thymocytes have to pass positive selection. Positive selection is believed to take place in the cortex. CD4+CD8+ double positive thymocytes test their TCR by interacting with self-peptide in the context of major histocompatibility complexes (MHC) expressed on cTEC. If the thymocytes fail to interact with the presented peptide they will die by neglect while low affinity / avidity interactions promote survival. It is estimated that less than 5% of developing T cells pass positive selection. While positive selection generates a self-restricted T cell repertoire, it also enriches for autoreactive thymocytes. To remove potentially dangerous T cells, positively selected cells have to face negative selection. Under physiological conditions it is believed that this process takes place in the medulla. Here mTEC as well as DC present self-peptide in the context of MHC molecules (MHCp) to the developing T cells. Thymocytes that interact with high affinity / avidity with presented with the presentet Ag will be removed from the T cell pool. Interestingly high affinity / avidity interactions can result in induction of regulatory T (Treg) cells as well.
I aim to characterize the kinetics by which T cell selection takes place by employing multi-photon intra-vital imaging.

2008 Conference Assistant at the Keystone Symposium “Leukocyte Trafficking”

2007-2010 DOC-fFORTE fellowship of the Austrian Academy of Sciences