Immunological memory protects the organism from pathogens it already defeated. This is achieved by a faster and more effective antigen-specific immune response. However, a misdirected, pathogenic immunological memory can also trigger immunopathology or autoimmunity. Immunological memory is embodied in long-lived antibody-secreting plasma cells and memory T and B cells that differentiate from naive precursors upon antigen exposure. An in-depth understanding of immunological memory is crucial for the development of efficient vaccination strategies and curative therapies of chronic immunopathology and autoimmunity.
The main goal of the Lichtenberg group is a molecular understanding of the generation, maintenance and functional capacity of immunological memory. We study the differentiation pathways and inductive signals of effector and memory cells. In addition, we analyze the stability and flexibility of memory cells and their effector mechanisms as well as their functional activity in vivo during inflammation and viral or parasite infections. Here, we examine molecular factors that regulate the longevity and functional quality of memory cells. Our studies are performed at single-cell level: We assess individual lymphocytes to obtain insight into the quantitative regulation of the molecular switches that control lymphocyte cell fate decisions.
T helper (Th) cells secrete defined amounts of specific cytokines to determine not only the type of a particular immune response, but also its intensity. By single-cell analysis and mathematical modeling, we could show that during their initial activation, individual Th cells not only ‘learn’ which cytokines they should produce, but also in which quantity (see figure). This Quantitative Cytokine Memory is stably maintained in memory Th cells and recalled upon secondary antigen encounter (Helmstetter et al., Immunity 2015). While analyzing the signals inducing quantitative programming of Th cells, we found that the alarmin interleukin (IL)-33 determines the intensity of Th type 1 (Th1) cell activation upon viral infection. IL-33 enhances the clonal expansion of Th1 cells and promotes their differentiation to potent, polyfunctional effector cells (Baumann et al., PNAS 2015). Moreover, we demonstrated a quantitative regulation of effector functions in individual Th cells via antagonizing key transcription factors. During parasite infections, hybrid Th1/Th2 cells are generated that stably co-express key Th1 and Th2 transcription factors. As these factors inhibit each other, a hybrid cell produces rather small amounts of Th1 and Th2 effector molecules. Yet, hybrid cells support both Th1 and Th2 immune responses while inducing less immunopathologic damage than classic Th1 or Th2 cells (Peine et al., PLoS Biol. 2013).