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Graff-Dubois, S.

Publications and source records attributed to Graff-Dubois, S..

2 recordsLinked to original sources
bioRxiv2023

Interleukin-1 regulates follicular T cells during the germinal center reaction

Antibody production by plasma cells and generation of long-term memory B-cells are positively regulated by Tfh cells and negatively regulated by Tfr cells in germinal centers. However, the precise role of Tfr cells in controlling antibody production is still unclear. We have previously shown that Tfh and Tfr cells both express IL-1R1, while only Tfr cells express the IL-1R2 decoy and IL-1Ra antagonist receptors. To study the role of these receptors in the regulation of the B cell response by Tfh and/or Tfr cells, we generated mice with knockout of IL-1 receptors in Tfh and/or Tfr cells and measured antibody production and cell activation upon immunization. We showed that IL-1{beta} concentration is increased in the draining lymph node after immunization. Antigen-specific antibody levels and cell activation phenotypes indicated that IL-1{beta} can activate both Tfh and Tfr cells through IL-1R1 stimulation. Surprisingly, IL-1R2 and IL-1Ra expression on Tfr cells does not block IL-1 activation of Tfh cells, but rather prevents IL-1/IL-1R1-mediated early activation of Tfr cells. IL-1Rs similarly regulate antibody response against autoantigens and its related pathophysiology in an experimental lupus model. Altogether, these results show that IL-1R1 inhibitory receptors expressed by Tfr cells prevent their own activation and suppressive function, thus licensing IL-1-mediated activation of Tfh cells after immunization. One Sentence SummaryFunctional knockout of IL-1 agonist (R1) and antagonist (R2 and Ra) receptors reveals that IL-1-R2 and -Ra on Tfr cells prevent their own early activation to license the expansion and activation of Tfh cells after immunization.

immunology↗
bioRxiv2021

The Autophagy Receptor TAX1BP1 (T6BP) is a novel player in antigen presentation by MHC-II molecules.

CD4+ T lymphocytes play a major role in the establishment and maintenance of immunity. They are activated by antigenic peptides derived from extracellular or newly synthesized (endogenous) proteins presented on the surface of antigen presenting cells (APCs) by the MHC-II molecules. The pathways leading to endogenous MHC-II presentation remain poorly characterized. We demonstrate here that the autophagy receptor, T6BP, influences both autophagy-dependent and -independent endogenous presentation of HIV- and HCMV-derived peptides. By studying the immunopeptidome of MHC-II molecules, we show that T6BP affects both the quantity and quality of peptides presented. T6BP silencing induces the mislocalization of the MHC-II-loading compartments and a rapid degradation of the invariant chain (CD74) without altering the expression and internalization kinetics of MHC-II molecules. We determined the interactome of T6BP, identified calnexin as a T6BP partner and show that CANX cytosolic tail is required for this interaction. Remarkably, calnexin silencing replicates the functional consequences of T6BP silencing: decreased CD4+ T cell activation and exacerbated CD74 degradation. Altogether, we unravel T6BP as a key player of the MHC-II-restricted endogenous presentation pathway and we propose one potential mechanism of action.

immunology↗