Biology subjects

Sekaly, R.-P.

Publications and source records attributed to Sekaly, R.-P..

2 recordsLinked to original sources

bioRxiv2020

Human follicular CD4 T cell function is defined by specific molecular, positional and TCR dynamic signatures.

The orchestrated interaction between follicular helper CD4 T cells (TFH) and germinal center (GC) B cells is crucial for optimal humoral immunity. However, the regulatory mechanisms behind spatial distribution and function of TFH is not well understood. Here, we studied human TFH cells and found that transitioning to a CD57hi TFH status was associated with distinct positioning in the GC, phenotype, transcriptional signatures, function and downregulation of their T-cell receptor (TCR). Single cell TCR clonotype analysis indicated a unidirectional transition towards the CD57hi TFH status, which was marked with drastic changes in the nature of immunological synapse formation where peripheral microclusters become dominant. Lack of central supra molecular activation cluster (cSMAC) formation in TFH synapse was associated with enhanced ubiquitination/proteasome activity in these cells. Our data reveal significant aspects of the tissue organization and heterogeneity of follicular adaptive immunity and suggest that CD57hi TFH cells are endowed with distinctive programming and spatial positioning for optimal GC B cell help. One Sentence Summaryhuman TFH cell heterogeneity

immunology↗

bioRxiv2020

TCF-1 regulates the stem-like memory potential of HIV-specific CD8+ T cells in elite controllers

Although many HIV cure strategies seek to expand HIV-specific CD8+ T cells to control the virus, all are likely to fail if cellular exhaustion is not prevented. A loss in stem-like memory properties (i.e., the ability to proliferate and generate secondary effector cells) is a key feature of exhaustion; little is known, however, about how these properties are regulated in human virus-specific CD8+ T cells. We found that virus-specific CD8+ T cells from humans and non-human primates naturally controlling HIV/SIV infection express more of the transcription factor, TCF-1, than non-controllers. HIV-specific CD8+ T cell TCF-1 expression correlated with memory marker expression and proliferative capacity and declined with antigenic stimulation. CRISPR-Cas9 editing of TCF-1 in human primary T cells demonstrated a direct role in regulating expansion capacity. Collectively, these data suggest that TCF-1 controls the stem-like memory properties of HIV-specific CD8+ T cells and provides a rationale for enhancing this pathway in T cell-based therapeutic strategies for HIV. One Sentence SummaryTCF-1 is highly expressed in HIV-specific CD8+ T cells from elite controllers and directly regulates human CD8+ T cell expansion capacity in response to T cell receptor stimulation.

immunology↗