Research Group

Innate Immunity Group Head: Werner HELD, Associate Member E-mail: werner.held@isrec.unil.ch Phone # : 41-21-692.5958/5979 Fax # : 41-21-692.5995 > Curriculum Vitae > Research Interests > Introduction > Current Projects > Selected publications

Curriculum Vitae

Werner Held studied Microbiology at the University of Bern and did his Ph.D. thesis in immunology in the laboratory of Profs. Ch. Muller and M. Hess in the Dept. of Pathology of the University of Bern (1987-90). He received his postdoctoral training in the laboratories of Drs. H. Acha-Orbea and H.R. MacDonald at the Lausanne Branch of the Ludwig Institute (1990-93) and in the lab of Prof. D.H. Raulet at the University of California at Berkeley (1993-96). In 1996 he received a START fellowship from the Swiss National Science Foundation and became Assistant Member at the Lausanne Branch of the Ludwig Institute. He was promoted to Associate Member of Ludwig Institute in 2002.

Research Interests

Research in my laboratory is focused on the understanding of

1. how Natural Killer (NK) cells discriminate normal from transformed or infected host cells
2. the development of functional NK cells from immature precursors

Introduction

Both T cells and NK cells play crucial roles in immunity to pathogens and cancer cells. Both cell types have the ability to determine whether a host cell is normal or diseased (i.e. infected or transformed) and whether it should be removed from the body. However, the recognition strategies used by T and NK cells are fundamentally different. Whereas T cells are able to generate almost indefinite numbers of receptors for almost indefinite numbers of foreign ligands, NK cells scan host cells for whether self-ligands are normally expressed. To this end NK cells use two classes of receptors, one that stimulates the NK cell, and another on that inhibits it. Upon the interaction with a host cell, it is the balance between inhibitory and activation signals that determines whether the NK cell will kill the host cell.

Inhibitory receptors expressed by NK cells preferentially recognize Major Histocompatibility Complex class I molecules (MHC-I). Their function is to prevent the lysis of cells that express MHC-I normally. Consequently, when target cells lose the expression of self-MHC-I, which is a common feature of infected or transformed cells, NK cells fail to receive inhibitory signals, shifting the balance towards NK cell activation ("missing-self recognition"). An alternative NK cell recognition strategy is that infected or stressed host cells induce the expression of endogenous self-molecules that serve as ligands for potent activating NK cell receptors ("induced-self recognition"). Importantly, many tumor cells express such ligands constitutively.

Current Projects

Formation of a NK cell receptor repertoire

Similar to antigen receptors on T and B lymphocytes, NK cells form a MHC-I receptor repertoire, which is subject to selection processes. In contrast to B and T cells, individual NK cells normally express more than one receptor and their distribution occurs in the absence of gene recombination events, which are required for the assembly of antigen receptor genes. Nevertheless, like antigen receptors, NK cell receptors are often expressed from only one of the two alleles (1). The acquisition of at least one of the inhibitory receptors (Ly49A) during NK cell development depends on the transcription factor TCF-1 (T cell factor 1) (2), a nuclear effector of the canonical wnt signaling pathway. Ly49A acquisition by some but not all NK cells seems to be due to rate limiting levels of TCF-1 in immature NK cells.

Regulation of NK cell function

Once acquired inhibitory MHC-I receptors influence the development of NK cells and determine in part their specificity (3). They inhibit the function of mature NK cells upon the interaction with their MHC-I ligands encountered on potential target cells.

Unexpectedly, we have found that the capacity to inhibit NK cells was drastically reduced when a MHC ligand and the corresponding inhibitory receptor were co-expressed on the same NK cell. Surprisingly we have found that the inhibitory Ly49A NK cell receptor not only bind to its MHC class I ligand expressed on potential target cells (i.e. in trans) but is constitutively associated with MHC class I in cis (i.e. on the same cell). Cis association and trans interaction occur via the same binding site. Consequently, cis association limits the number of Ly49A receptors available for binding MHC class I on target cells, thereby dampening NK cell inhibition via Ly49A (4).

By lowering the threshold at which NK cell activation exceeds NK cell inhibition, cis interaction seems to allow an optimal discrimination of normal and infected or transformed host cells.

Additional projects address the contribution of specific of NK cell activation pathways for the recognition of normal and aberrant host cells.

Lymphocyte development

T lymphocytes develop and mature in the thymus from immature bone marrow-derived precursors. T cell development requires appropriate signals at sequential developmental stages that depend on functionally rearranged T cell receptor (TCR) b chains and TCR ab heterodimers, respectively. While the TCR for antigen plays a crucial role, TCR-independent signals are also required for T cell development. Recent evidence suggests that the Wnt signaling pathway plays an important role at multiple distinct stages of T cell maturation. Indeed, the development of T cells is very inefficient in the absence of TCF-1. Indeed, our data show that T cell development is dependent on the interaction of TCF-1 with its co-activator b-catenin, a signaling intermediate of the canonical wnt pathway. One important effect of this interaction is that immature thymocytes are protected from rapid spontaneous cell death. This is mediated by Bcl-xL, a molecule that prevents thymocyte death (5).

In addition to T cells, we have shown that NK cell development is also dependent on TCF-1. This suggests a close developmental relationship of T and NK cells and raises the question whether T cells and NK cells share a common TCF-1-dependent precursor.

Selected publications

1. Held, W., Roland, J. and Raulet, D.H. 1995. Allelic exclusion of Ly49 family genes encoding class I MHC-specific receptors on NK cells. Nature 376:355-358. [PubMed]

2. Held, W., Kunz, B., Lowin-Kropf, B., van de Wetering, M. and Clevers, H. 1999. Clonal acquisition of the Ly49A NK cell receptor is dependent on the trans-acting factor TCF-1. Immunity 11:433-442.

3. Held, W, Coudert, J.D. and Zimmer, J. 2003. The NK cell receptor repertoire: Formation, adaptation and exploitation. Curr. Op. Immunol. 233-237.

4. Doucey, M.-A., Scarpellino, L., Zimmer, J., Guillaume, P., Luescher, I.F., Bron, C., Held, W. 2004. Cis-association of Ly49A with MHC class I restricts trans-interaction and NK cell inhibition. Nature Immunol. 5: 328-336.

5. Ioannidis, V., Beermann, F., Clevers, H. and Held, W. 2001. The -catenin- TCF-1 pathway ensures CD4+ CD8+ thymocyte survival. Nature Immunol. 2:691-697.