Biology subjects

Oberle, S.

Publications and source records attributed to Oberle, S..

4 recordsLinked to original sources

bioRxiv2021

T cell receptor and IL-2 signaling strength control memory CD8+ T cell functional fitness via chromatin remodeling

Cognate antigen signal controls CD8+ T cell priming, expansion size and effector versus memory cell fates, but it is not known if and how it modulates the functional features of memory CD8+ T cells. Here we show that the strength of T cell receptor (TCR) signaling determines the requirement for interleukin-2 (IL-2) signals to form a pool of memory CD8+ T cells that competitively re-expand upon secondary antigen encounter. Combining strong TCR and intact IL-2 signaling synergistically induces genome-wide chromatin accessibility in regions targeting a wide breadth of biological processes, consistent with their greater functional fitness. Chromatin accessibility in promoters of genes encoding for stem cell, cell cycle and calcium-related proteins correlated with faster intracellular calcium accumulation, initiation of cell cycle and more robust expansion. High-dimensional flow-cytometry analysis also highlights higher subset diversity and phenotypes. These results formally establish that epitope selection in vaccine design strongly impacts memory CD8+ T cell epigenetic programming and functions. One Sentence SummaryThe strength of antigenic and interleukin 2 signals received by CD8+ T cells during vaccination epigenetically programs their ability to form functional memory.

immunology↗

bioRxiv2019

Progressive differentiation of memory CD8 T cells in the cervicovaginal tissue

Tissue-resident memory CD8 T cells (CD8 TRM) are critical for maintaining barrier immunity. CD8 TRM have been mainly studied in the skin and gut with recent studies suggesting that the signals that control tissue-residence and phenotype are highly tissue-dependent. We examined the T cell compartment in healthy human cervicovaginal tissue (CVT) and found that most CD8 T cells were granzyme B+ and TCF-1-. To address if this phenotype is driven by CVT tissue-residence, we used a mouse model to control for environmental factors. Using localized and systemic infection models, we found that CD8 TRM in the mouse CVT gradually acquired a granzyme B+, TCF-1- phenotype as seen in human CVT. In contrast to CD8 TRM in the gut, these CD8 TRM were not stably maintained regardless of the initial infection route, which led to reductions in local immunity. Our data show that residence in the CVT is sufficient to progressively shape the size and function of its CD8 TRM compartment. SummaryThe tissue-resident memory (TRM) CD8 T cell compartment in human and mouse cervicovaginal tissue (CVT) is remarkably similar. The CVT TRM compartment is maintained autonomously and does not reach phenoypical or numerical equilibrium. The numerical decline leads to impaired viral control in a secondary challenge.

immunology↗

bioRxiv2018

Attenuation of chronic antiviral T cell responses through constitutive COX2-dependent prostanoid synthesis by lymph node fibroblasts

Fibroblastic reticular cells (FRC) of lymphoid T zones actively promote T cell trafficking, homeostasis and expansion, but can also attenuate excessive T cell responses via inducible nitric oxide and constitutive prostanoid release. It has remained unclear under which conditions these FRC-derived mediators can dampen T cell responses and whether this occurs in vivo. Here we confirm that murine lymph node FRC produce prostaglandin E2 (PGE2) in a cyclooxygenase-2 (COX2)-dependent and inflammation-independent fashion. We show that this COX2/PGE2 pathway is active during both strong and weak T cell responses, in contrast to nitric oxide which only comes into play during strong T cell responses. In chronic infections in vivo, PGE2-receptor signaling in virus-specific CD8 T cells was shown by others to suppress T cell survival and function. Using CCL19cre x COX2flox/flox mice we now identify CCL19cre+ FRC as the critical source of this COX2-dependent suppressive factor, suggesting PGE2-expressing FRC within lymphoid tissues are an interesting therapeutic target to improve T cell mediated pathogen control during chronic infection.

immunology↗

bioRxiv2017

Strong homeostatic TCR signals induce formation of self-tolerant virtual memory CD8 T cells

Virtual memory T cells are foreign antigen-inexperienced T cells that have acquired memory-like phenotype and constitute for 10-20% of all peripheral CD8+ T cells in mice. Their origin, biological roles, and relationship to naive and foreign antigen-experienced memory T cells are incompletely understood. By analyzing TCR repertoires and using retrogenic monoclonal T-cell populations, we show that virtual memory T cells originate exclusively from strongly self-reactive T cells. Moreover, we show that the stoichiometry of the CD8 interaction with Lck regulates the size of the virtual memory T-cell compartment via modulating the self-reactivity of individual T-cell clones. We propose a so far unappreciated peripheral T-cell fate decision checkpoint that eventually leads to the differentiation of highly self-reactive T cells into virtual memory T cells. This underlines the importance of the variable level of self-reactivity in polyclonal T cells for the generation of functional T-cell diversity. Although virtual memory T cells descend from the highly self-reactive clones and acquire a partial memory program, they do not show higher capacity to induce autoimmune diabetes than naive T cells. Thus, virtual memory T cells are not generally more responsive than naive T cells, because their activity highly depends on the immunological context.\n\nSummaryWe conclude that virtual memory T cells are formed from self-reactive CD8+ T cells in a process regulated by CD8-Lck stoichiometry. Despite their self-reactivity and partial memory differentiation program, virtual memory T cells did not show a strong autoimmune potential.

immunology↗