Dynamic Adoption of Anergy by Antigen-Exhausted CD4 &lt;sup&gt;+&lt;/sup&gt; T Cells

Trefzer, Anne; Kadam, Pallavi; Wang, Shu-Hung; Pennavaria, Stefanie; Lober, Benedikt; Kranich, Jan; Brocker, Thomas; Irmler, Martin; Beckers, Johannes; Straub, Tobias; Obst, Reinhard

doi:10.2139/ssrn.3549537

Cited by 1 publication

(3 citation statements)

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“…Intriguingly Lag3, Tigit and IL-10, appeared as a delayed and transient module, largely unique to stronger TCR signalling groups. Similar observations have been observed in chronic tolerance models (Burton et al, 2014) and in models of persisting antigen (Trefzer et al, 2021).…”

Section: Discussionsupporting

confidence: 86%

“…Similar results are reported for extracellular signal-regulated kinase (ERK) activation (Altan-Bonnet and Germain, 2005; Das et al, 2009). Nonetheless, despite these digital behaviours, it is reported that TCR signal strength can lead to graded expression of molecules such as interferon regulatory factor 4 (IRF4) (Conley et al, 2020), Nr4a1 (Moran et al, 2011) and co-inhibitory receptors (Trefzer et al, 2021). Recent data show that under reduced TCR signal strength levels, nuclear factor kappa B (NF-κB) activation may be analogue (Gallagher et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

“…CD8 + T cell studies have reported that TCR signal strength does not influence their end stage cytolytic capacity in vitro (Richard et al, 2018). However, analysis of thymic CD4 + T cell development clearly demonstrates that strong and persistent TCR signals drive Foxp3 + Treg development (Bending et al, 2018b; Jennings et al, 2020; Moran et al, 2011), and antigen affinity and dose have distinct effects on peripheral CD4 + T cell transcriptional programmes (Keck et al, 2014; Trefzer et al, 2021). Understanding how graded responses to TCR signal strength can modulate T cell function is likely to be critical to understanding mechanisms behind immunotherapies.…”

Section: Introductionmentioning

confidence: 99%

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Antigen and Checkpoint Receptor Recalibration of T Cell Receptor Signal Strength

Elliot

Jennings

Lecky

et al. 2021

Preprint

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How T cell receptor (TCR) signal strength modulates T cell function and to what extent this is modified by immune checkpoint blockade (ICB) are key questions in immunology. Using Nr4a3-Tocky mice as a digital read-out of NFAT pathway activity, we identify the rapid quantitative and qualitative changes that occur in CD4+ T cells in response to a range of TCR signalling strengths. We demonstrate that the time and dose dependent programming of distinct co-inhibitory receptors rapidly re-calibrates T cell activation thresholds. By developing a new in vivo model, we analyse the immediate effects of ICB on T cell re-activation. Our findings reveal that anti-PD1 but not anti-Lag3 immunotherapy leads to an increased TCR signal strength. We define a strong TCR signal metric of five genes specifically upregulated by anti-PD1 in T cells (TCR.strong), which can stratify clinical outcomes during anti-PD1 monotherapy in melanoma patients. Our study therefore reveals how analysis of TCR signal strength – and its manipulation – can provide powerful metrics for monitoring outcomes to immunotherapy.

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Section: Discussionsupporting

confidence: 86%