George, L. S. | Search bioRxiv

bioRxiv2024

Interferonγ and IL-27 positively regulate type 1 regulatory T-cell development during adaptive tolerance

Strong T-cell receptor (TCR) and IL-27 signalling influence type-1 regulatory (Tr1) T-cell development but whether other signals determine their differentiation is unclear. Utilising Tg4 TCR transgenic mice we established a model for rapid Tr1 cell induction. A single high dose of [4Y]-MBP peptide drove the differentiation of Il10+ T-cells with bona fide Tr1 cell protein and mRNA signatures. Kinetic transcriptional analysis revealed that the Tr1 cell module was transient and preceded by a burst of Ifng transcription in CD4+ T-cells. Neutralisation of IFN{gamma} reduced Tr1 cell frequency and strong TCR signalling markers, which was correlated with reduced macrophage activation. Antibody depletion experiments inferred that T-cells - but not NK cells - provided the relevant source of IFN{gamma}. Additionally, we show that blocking IL-27 in combination with IFN{gamma} neutralisation additively reduced Tr1 cell frequency in vivo. These findings reveal that during strong tolerogenic TCR signalling IFN-{gamma} has a non-redundant regulatory role in augmenting the differentiation of Tr1 cells in vivo.

immunology↗

bioRxiv2024

Lag3 and PD-L1 govern T cell receptor signal duration in adaptively tolerised CD4+ T cells

Lag3 and PD-1 are immune checkpoints that regulate T cell responses and are current immunotherapy targets. Yet how they function to control early CD4+ T cell activation remains unclear. Here, we show that the PD-1 and Lag3 pathways exhibit layered control of the early CD4+ T cell activation process, with the effects of Lag3 more pronounced in the presence of PD-1 pathway co-blockade (CB). RNA-sequencing revealed that CB drove an early NFAT-dependent transcriptional profile, including promotion of ICOShi T follicular helper (Tfh) cell differentiation. NFAT pathway inhibition abolished CB-induced upregulation of NFAT-dependent co-receptors ICOS and OX40, whilst unaffecting the NFAT-independent gene Nr4a1. Mechanistically, Lag3 and PD-1 pathways functioned additively to regulate the duration of T cell receptor (TCR) signals during CD4+ T cell re-activation. Our data therefore reveal that PD-1 and Lag3 pathways converge to additively regulate TCR signal duration and NFAT-dependent transcriptional activity during early CD4+ T cell re-activation. HighlightsO_LIPD-1 and Lag3 pathways exhibit layered control of early CD4+ T cell activation C_LIO_LITheir co-blockade enhances NFAT-dependent TCR transcriptional programmes C_LIO_LIInhibition of NFAT signalling reverses the functional effects of PD-1 and Lag3 co-blockade C_LIO_LIMechanistically, PD-1 and Lag3 function to additively regulate TCR signal duration during re-activation of CD4+ T cells C_LI

immunology↗