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The overall goal of our research is to understand at a genome-wide level how T cells provide protection against infectious diseases and cancer. Toward this goal, our work is focused in two major research lines, which are:

1. Molecular Regulation of Antigen-Specific T Cell Responses
It is now well established that T cells play a key protective role during microbial infection and cancer. However, T cells express very potent effector molecules that can also cause substantial damage to healthy tissues, and therefore several regulatory mechanisms have evolved to inhibit T cell functionality. The downside of this T cell inhibition is that it can eventually facilitate the persistence of pathogens or tumour cells, thereby aiding the development of chronic infections and cancer. So, to help treat diseases such as Tuberculosis, HIV/AIDS or Melanoma, there is now a large demand for novel therapeutic strategies to block T cell inhibition. In this context, we have recently identified a new inhibitory mechanism of clonally expanded T cells that operates via the sustained downregulation of antigen receptor expression in proportion to the strength of the initial antigen recognition. Currently, we are investigating the molecular pathways driving this sustained T cell antigen receptor downregulation, ultimately aiming to maximize the therapeutic potential of T cell responses.

2. Host and Pathogen Factors in Protective Immunity to Tuberculosis
Tuberculosis remains a top 10 cause of death worldwide and has been very difficult to control due to an increase in drug-resistant strains and the absence of an effective vaccine. A major obstacle for successful vaccine development is the lack of clear immunological correlates of protection. Unravelling the mechanistic basis of protective T cell responses has proven highly challenging, primarily due to a lack of suitable experimental models. To address these limitations, we have developed a new protection model amenable to high-throughput genetic manipulation, using transgenic Mycobacterium tuberculosis-specific CD4+ T cells. We are currently combining this model with adoptive cell transfers and functional genomics tools to elucidate the T cell-mycobacterial interplay at the primary site of disease, the lung. Understanding protective immune mechanisms in tuberculosis will provide new avenues to target this refractory infectious killer.

For contact and enquiries, please send an e-mail to: j.w.vanheijst@amc.nl