ORCID Profile
0000-0003-1996-1672
Current Organisation
University of Zurich
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Publisher: American Society for Clinical Investigation
Date: 28-09-2015
DOI: 10.1172/JCI81187
Publisher: Frontiers Media SA
Date: 13-06-2018
Publisher: Cold Spring Harbor Laboratory
Date: 29-07-2022
DOI: 10.1101/2022.07.29.501979
Abstract: Harnessing the potential of commensal bacteria for immunomodulatory therapy in the gut requires the identification of conditions that modulate immune activation towards incoming colonizing bacteria. In this study, we used the commensal Bacteroides thetaiotaomicron (B.theta) and combined it with B.theta -specific transgenic T cells, in the context of defined colonization of gnotobiotic and immunodeficiency mouse models, to probe the factors modulating bacteria-specific T cell activation against newly colonizing bacteria. After colonizing germ-free (GF) and conventionally raised (SPF) mice with B.theta, we only observed proliferation of B.theta -specific T cells in GF mice. Using simple gnotobiotic communities we could further demonstrate that T-cell activation against newly colonizing gut bacteria is restricted by previous bacteria colonization in GF mice. However, this restriction requires a functional adaptive immune system as Rag1 -/- allowed B.theta -specific T cell proliferation even after previous colonization. Interestingly, this phenomenon seems to be dependent on the type of TCR-transgenic model used. B.theta -specific transgenic T cells also proliferated after gut colonization with an E.coli strain carrying the B.theta-specific epitope. However, this was not the case for the SM-1 transgenic T cells as they did not proliferate after similar gut colonization with an E.coli strain expressing the cognate epitope. In summary, we found that activation of T cells towards incoming bacteria in the gut is modulated by the influence of colonizing bacteria on the adaptive immune system of the host.
Publisher: The American Association of Immunologists
Date: 15-04-2013
Abstract: CD8+ T cells are fundamental for immune-mediated clearance of viral infections and contribute to immune pathology in autoimmune diseases such as type 1 diabetes. To execute these functions, CD8+ T cells must differentiate into CTLs, a process that is precisely regulated by a variety of cytokines, costimulatory molecules, and transcription factors. IL-21 is an IL-2 family cytokine and a growth factor for multiple lymphocyte effector lineages, including cytotoxic CD8+ T cells. Recent studies demonstrate that loss of IL-21 signaling results in reduced viral clearance in models of lymphocytic choriomeningitis virus infection, and also protection from type 1 diabetes in the NOD model. This is most likely the result of impaired CD8+ CTL function in the absence of IL-21 signaling. Currently, the mechanisms by which IL-21 promotes CTL differentiation in CD8+ T cells remain unclear, particularly the identity of the relevant transcription factor(s). We show that IL-21 promotes CTL function in vitro and killing of pancreatic islets in vivo via the use of transgenic mice expressing IL-21 in pancreatic β cells. We demonstrate that IL-21 induces the expression of the transcription factor T-bet in CD8+ T cells, predominantly via STAT1, and that T-bet is required for the induction of cytolytic molecules, including perforin and granzyme B in response to IL-21. Finally, we show that IL-21–induced CTL function is T-bet dependent, as T-bet deficiency results in defective IL-21–dependent cytotoxicity in CD8+ T cells in vitro and in vivo. Thus, IL-21 drives CD8+ CTL differentiation via the actions of the transcription factor T-bet.
Publisher: Wiley
Date: 20-12-2011
Abstract: Two subsets of CD8(+) T cells are generated early during an immune response one of these subsets forms the memory pool, known as memory precursor effector cells (MPECs), identified by high expression of CD127 and low expression of KLRG1, whereas the other subset forms short-lived effector cells (SLECs) identified by low expression of CD127 and high expression of KLRG1. Here, we studied in vivo the role of type-I IFN in this fate decision. We found that under priming conditions dominated by type-I IFN, as observed in lymphocytic choriomeningitis virus (LCMV) infection, type-I IFN signaling directly impacted the regulation of T-bet and thus the early fate decision of CD8(+) T cells. In the absence of type-I IFN signaling, CD8(+) T cells failed to form SLECs but could form MPECs that give rise to functional memory CD8(+) T cells. Together, these findings identify type-I IFN as an important factor driving SLEC differentiation and thus instructing the early ision between the effector and memory precursor CD8(+) T-cell pool.
No related grants have been discovered for Nicole Joller.