The mechanism of effector T cell formation
The unifying theme of this research line is the regulation of effector/memory T cell formation in humans and mice (Figure 1). The goals are to determine the contribution of costimulatory molecules and transcription factors in the differentiation towards effector T cells and to identify functionally distinct T cell subsets and their role in normal and pathophysiological immune reactions. Regarding the latter, we have found that the human lung harbors a resident subset of CD8+ T cells expressing CD103 (aE integrin) and that this subset is highly enriched for CD8+ T cells specific to respiratory viruses, such as influenza, but not to systemic viruses, such as the Epstein Barr virus and the cytomegalovirus. CD103+CD8+ T cells produced large amounts of IFNγ, but did not contain perforin nor granzyme B, which indicates that this pool of resident CD8+ T cells can provide a rapid response to viral infection without inducing cytotoxic damage to the delicate epithelial barrier (Piet et al., 2011).
Following a long-standing interest in the consequences of T cell costimulation through CD27 and its ligand CD70, we have recently found that CD27 triggering on CD4+ T cells does not provide instructive signals for a specific CD4+ T cell subset, but, depending on the cytokine milieu and genetic background, supports Th1 cell formation, while it inhibits the formation of Th17, but not Th2 cells (Libregts et al., Imm Letters 2011). Moreover, we established that CD27-driven costimulation lowers the threshold of T cell receptor activation for CD8+ T cells and enables responses against low-affinity antigens. We therefore propose that CD27-driven costimulation is a strategy to generate memory clones that have potential reactivity to a wide array of mutable pathogens (Van Gisbergen et al., 2011).
Finally, based on transcriptome analysis of primary effector CD8+ T cells in humans, we have identified a novel molecule, ZNF683, that is strongly upregulated in effector CD8 T cells (Hertoghs et al., J Clin Invest 2010). The expression profile of ZNF683 suggests that this factor is involved in modulating CD8 T cell differentiation. Based on its high homology to the transcription factor Blimp-1, we have renamed ZNF683 as HOBIT, for Homologue of Blimp-1 in T cells. Expression analysis in humans revealed that Hobit is mainly expressed in effector CD8 T cells, NK cells and cytotoxic CD4 T cells. Interestingly, this pattern was markedly different in mice, where we found Hobit to be expressed predominantly in NKT cells. Detailed analysis of Hobit-deficient mice indicated that Hobit is required for terminal differentiation of NKT cells and for the stimulus-induced cytolytic effector function (Van Gisbergen et al. Nat. Immunol. 2012). Based on our findings we postulate that Hobit is a novel master regulator of cytotoxicity in lymphocytes.
Figure 1: Differentiation of naive T cells towards effector and memory T cells is strongly dependent on the interactions of the naive T cell with the activated dendritic cell that presents the cognate antigen. Our lab investigates the underlying molecular mechanism that regulates the quantity and quality of the ensuing T cell response.
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