We consider T cells as the most fascinating cells in our bodies. Unlike the vast majority of other somatic cells, each T cell is genetically unique, because it shuffles the pieces of DNA that encode for its antigenic receptor. It means that each single T cell has its unique antigenic receptor with a unique specificity. We can compare the T cells to an army of soldiers, each of them carrying a unique weapon used in a specific situation. When the organism is infected with a pathogen, there are always a couple of T cells with the right weapon/receptor that initiate the adaptive immune response. On the other hand, too much of T-cell reactivity might induce friendly fire, or autoimmunity in immunological terms.
Our long-term research interest is to understand how the T-cell antigenic receptor (TCR) and other receptors on T cells transduce the signals from outside to inside the cells. In particular, we focus on the role of CD4/CD8 coreceptors and Lck in the TCR signaling. We also use mass-spectrometry to identify proteins that are involved in the signal transduction of inhibitory and costimulatory receptors. These receptors are very powerful, because they play key roles in the T-cell decision to initiate the immune response or ignore the signals coming from the TCR. Clinical modulations of these receptors show very promising results in the cancer immunotherapy. We aim to uncover novel players in this process that might represent new targets for such therapy.
Besides the huge heterogeneity of individual T-cell clones, there are diverse subsets of T cells that differ in their gene expression programs. We are specifically interested in the biology of virtual memory T cells, i.e. cells that ‘pretend’ to remember previous infections, which never happened. For this reason, a term ‘fake memory’ T cells might better describe this subset. Anyway, we are trying to resolve the immunological role of these cells. However, virtual memory T cells are not the only mysterious population. There is an enormous number of proposed CD8+ T cell subsets, but most of them are only poorly characterized. We received a generous grant from the European Research Council to use single cell RNA sequencing to ´rediscover´ the CD8+ T-cell subsets. We developed a mouse model to study the specific function of individual subsets during infection, autoimmunity, and cancer.
IL-17 is a proinflammatory cytokine (signaling molecule) produced by a specific type of T cells. This cytokine contributes to protection from candida and staphylococcus infection, but is also involved in the pathology of autoimmune diseases. We developed a novel approach for the analysis of the IL-17 receptor proximal signaling complex and identified novel players in the IL-17 signal transduction. Based on our data, we proposed a novel mechanism of how the IL-17R might signal, which has not been shown for any cellular receptor so far. We are currently working on addressing this hypothesis and on evaluating the importance of individual molecules in the IL-17R signaling complex.
Bardet-Biedl Syndrome (BBS) is a multiorgan genetic disease, usually caused by dysfunction of any of the subunits of a protein transport complex BBSome. BBSome is important for the trafficking of selected receptors into and out of the primary cilium, a specialized protrusion-like cellular organelle. We aim to understand how BBSome assembles in living cells. For this research, we are employing advanced microscopy techniques. There are multiple possible links between the BBS and the immune system that have not been addressed yet. We are exploring these directions by using clinical data, a mouse model for BBS, and cell lines.
If you are interested in these topics and if you would like to join our group, please, check the open positions.
- SNSF, PROMYS – T cell calculus: how T cells measure and interpret antigenic signals in health and disease, 2016-2020, O. Štěpánek
- EMBO, EMBO Installation Grant – Antigenic signalling and fate decisions in T cells, 2016-2018, O. Štěpánek
- GACR, 16-09208Y – T cell receptor signaling and fate decisions made by peripheral T cells in homeostasis and during inflammation, 2016-2018, O. Štěpánek
- GACR, 17-27355Y – Elucidation of molecular mechanisms guiding assembly and function of IL-17-receptor signaling complex, 2017-2019, P. Dráber
- GACR, 17-20613Y – BBSome and actin interplay in ciliogenesis and formation of the immunological synapse, 2017-2019, M. Huranová