Biology subjects

Lebel, M.-E.

Publications and source records attributed to Lebel, M.-E..

3 recordsLinked to original sources

bioRxiv2026

The Notch signaling pathway is a master regulator of CD8+ T cell exhaustion and differentiation during chronic infection

During chronic infection, the persistence of antigen and inflammation leads to the differentiation of CD8+ T cells into an exhausted state characterised by expression of inhibitory receptors (IRs) and the progressive loss of T cell functions. Among the different subsets of exhausted CD8+ T (Tex) cells, Tex progenitors expressing SLAMF6 and the transcription factor TCF-1 (TCF-1+) give rise to Tex effector-like cells expressing CX3CR1 and Tex terminal cells expressing CD101. PD-1/PD-L1 blockade acts on TCF-1+ Tex progenitor cells and promotes their differentiation into Tex effector-like cells. The molecular events controlling CD8+ Tex cell differentiation are still poorly defined. As Notch signaling may be sustained during chronic infection by persistent TCR stimulation and inflammation, we tested whether Notch signaling influences CD8+ T cell exhaustion. Using mice lacking (N1N2{triangleup}/{triangleup}) or not (N1N2fl/fl) Notch1/2 expression only in mature CD8+ T cells, we showed that the absence of Notch signal causes severe CD8+ T cell exhaustion during chronic LCMV infection. N1N2{triangleup}/{triangleup} Tex cells express higher levels of IRs and are less functional when compared to their wild-typee counterpart. In the absence of N1N2 receptors, Tex progenitor and Tex terminal cells accumulate and Tex cells cannot be reinvigorated by PD-1/PD-L1 blockade. We further demonstrated that Notch signaling is essential to promote the differentiation of Tex progenitors into Tex effector-like cells. Moreover, Notch signals, provided by stromal cells expressing the ligands Delta-like 1 and 4, are necessary during all stages of the infection to prevent severe exhaustion. Single-nucleus RNA and ATAC multiome profiling identifies Notch signaling as a critical role on effector transcriptional programming in exhausted CD8 T cells. Loss of Notch signaling impairs transcriptional program associated with migration and perception of CD4+ T cell help. Together, these alterations drive the differentiation of Tex progenitor cells toward a terminally exhausted Tex fate.

immunology↗

bioRxiv2024

CD271 restrains the B1b cell antibody response in a T cell dependent manner

Co-signaling molecules modulate T cell function and are essential to control the duration and amplitude of immune responses. These molecules belong to the immunoglobulin and tumor necrosis factor receptor (TNFR) superfamilies and have been extensively studied; however, the immunomodulatory role of several family members remains unknown. We show that CD271 (also known as p75 or NGFR), a TNFR superfamily member, is highly expressed on peritoneal B1 B cells, but not on conventional (B2) B cells at steady state. CD271 expression by B cells specifically restrains the response to T cell-independent type 2 antigens (TI-2). B1 cell-expressed CD271 maintains peritoneal CD4+ T cell quiescence, and augmented antibody responses to TI-2 antigens in CD271-deficient mice are dependent on CD4+ T cells. This increase in antibody production correlates with improved bacterial neutralization in vitro and survival after bacterial challenge in vivo. Further, our results suggest that CD271 can directly inhibit mouse and human T cell activity to the same extent as PD-L1, a known, negative regulator of T cell function. These results establish CD271 as a co-inhibitory molecule that could be targeted to improve the efficacy of vaccines against pathogenic encapsulated bacteria and to broadly modulate the T cell response in therapeutic contexts. eTOC summaryLebel et al. identify an unexpected role for CD271, a neurotrophin receptor, in directly inhibiting T cell function. B1 cell-expressed CD271 maintains CD4+ T cell quiescence; in the absence of CD271, T cells bolster antibody production to T-independent antigens, enhancing the response to encapsulated bacteria.

immunology↗

bioRxiv2021

Pre-existing chromatin accessibility and gene expression differences among naïve CD4+ T cells influence effector potential

CD4+ T cells have a remarkable potential to differentiate into diverse effector lineages following activation. Here, we probed the heterogeneity present among naive CD4+ T cells before encountering their cognate antigen to ask whether their effector potential is modulated by pre-existing transcriptional and epigenetic differences. Using single-cell RNA sequencing, we showed that key drivers of variability are genes involved in T cell receptor (TCR) signaling. Using CD5 expression as a read-out of the strength of tonic TCR interactions with self-peptide MHC, and sorting on the ends of this self-reactivity spectrum, we find that pre-existing transcriptional differences among naive CD4+ T cells impact follicular helper cell (TFH) versus non-TFH effector lineage choice. Moreover, our data implicate TCR signal strength during thymic development in establishing differences in naive CD4 T cell chromatin landscapes that ultimately shape their effector potential.

immunology↗