Research Interests
Adaptive immunity, lymphocyte development, immunological tolerance, T cell receptor signaling, T cell fate decisions, autoimmunity, immune regulations, T cell homeostasis, cytotoxic T cells, regulatory T cells
Our research focuses on understanding of how antigenic signals determine fate decisions of T cells during their development, homeostasis, and immune responses. We cover a wide range of processes, from molecular determinants of T cell responses to cellular interactions in animal models of infection and autoimmunity. At the moment, we are working on three specific projects in the field of regulatory T cells, formation of self-tolerant and immune-sufficient T cell repertoire, and origin and function of ‘virtual’ memory T cells. The long-term aim of our lab is to understand how T cell receptor signals are initiated and how the primary sequence of TCR-encoding genes predetermines various T cell fate decisions during a life-time of an individual.
1. Hyperactivity of self-reactive CD8+ T cells and impaired immune suppression by regulatory T cells (Tregs) are believed to be associated with the development of certain autoimmune disorders, like type I diabetes or multiple sclerosis. We would like to elucidate whether there is a link between these two phenomena, i.e whether regulatory T cells prevent autoimmunity by suppressing self-reactive CD8+ T cells.
For this project, we use an animal model of experimental type I diabetes, based on adoptive transfer of ovalbumin-reactive monoclonal CD8+ OT-I T cells into a transgenic RIP.OVA host expressing ovalbumin in insulin-secreting cells. After being primed with ovalbumin or related antigen, OT-I eventually differentiate into tissue infiltrating effector T cells and induce lethal autoimmunity. By comparing Treg-replete or -depleted hosts, we investigate whether Tregs establish peripheral tolerance by increasing the self-antigen dose, the self-antigen affinity, and/or the number of precursor self-reactive cells required for the onset of autoimmunity. Moreover, we elucidate how conventional CD4+ T cells influence the activation and effector function of self-reactive CD8+ T cells. In the next step, we are going to uncover suppressive mechanisms (e.g. IL-2 stealing, direct killing, inhibiting costimulation) that Tregs use to prevent CD8+ T cell-mediated cytotoxicity.
2. We have previously shown that the interaction between a kinase, Lck and CD4 or CD8 T-cell coreceptors plays a crucial role for setting the threshold for negative selection of thymocytes and establishing the central immunological tolerance. Now, we are investigating the importance of the stoichiometry of the Lck-CD4 and Lck-CD8 for fate decisions made by mature T cells. Our preliminary data indicate that the Lck-CD4 and Lck-CD8 coupling frequency is dynamically regulated during T cell development. Our mathematical model predicts that CD8+ T cells, but not CD4+ T cells, increase their responsiveness to antigens at or just below the affinity threshold for negative selection. We hypothesize that the evolution tuned the stoichiometry of the Lck-CD4 and Lck-CD8 interaction to achieve optimal balance between self-tolerance and efficient responses to tumors and pathogens independently for CD8+ cytotoxic and CD4+ helper T cells. We are now addressing these predictions experimentally using various approaches focused on T cell activation and signal transduction, T cell homeostasis, autoimmunity, anti-tumor and anti-bacterial response.
3. Recent studies have revealed that T cell homeostasis plays an important role in immune responses towards self- and foreign-antigens. However, the mechanisms underlying T cell homeostasis and subsequent immune responses are incompletely understood.
So far enigmatic ‘virtual’ memory CD8+ T cells show memory-like phenotype, but they are generated via an unknown homeostatic process and thus, do not represent true immunological memory. Other studies have shown that self-reactivity of T cells largely determines how particular clones respond during immune responses against invading pathogens.
Based on our preliminary data, we hypothesize that the ‘virtual’ memory T cells originate from naïve peripheral T cells with relatively high self-reactivity. We are now addressing this hypothesis using a panel of approaches involving in vitro and in vivo activation of transgenic monoclonal T cells, in vivo models of autoimmunity and infection, global gene expression profiling and deep TCR sequencing. We also aim to elucidate whether ‘virtual’ memory T cells exist in humans.