Dynamic adoption of anergy by antigen-exhausted CD4+ T cells

Abstract

Highlights d Th1 functionalities are reduced by persisting antigen in doseand time-dependent manner d Signaling pathways are adjusted to persisting antigen with different sensitivities d Gene transcription is dynamically and reversibly adjusted to persisting antigen d About half of the genes affected by antigen persistence respond in a dose-specific manner

Antigen and checkpoint receptor engagement recalibrates T cell receptor signal strength

“…Lag3, Tigit, and Il10 appeared as a delayed and transient module, which was a feature of the stronger TCR signaling group. Similar observations have been observed in chronic tolerance models (Burton et al, 2014) and in models of persisting antigen (Trefzer et al, 2021).…”

“…Similar results are reported for extracellular signal-regulated kinase (ERK) activation ( Altan-Bonnet and Germain, 2005 ; Das et al., 2009 ). Nonetheless, despite these digital behaviors, 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 ). Reduced TCR signal strength can also drive graded nuclear factor kappa B (NF-κB) activation ( Gallagher et al., 2020 ).…”

“…TCR signal strength does not influence CD8 + T cell 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 + regulatory T (Treg) cell 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 cells ( Keck et al., 2014 ; Trefzer et al., 2021 ). Understanding how graded responses to TCR signal strength can modulate T cell function will likely be critical to understanding mechanisms behind immunotherapies.…”

Spatial Profiles of Intratumoral PD-1+ Helper T Cells Predict Prognosis in Head and Neck Squamous Cell Carcinoma

“…In agreement with previous studies indicating that PD-1 + T cells is associated with poor prognosis in breast cancer before the era of immunotherapy (37,38), our data demonstrate that a high density of PD-1 + helper T cells in tumor cell nests was a significant poor prognostic factor in HNSCC that was not treated by immunotherapy (Figures 3, 4). Given that PD-1 expression on T cells is induced by continuous exposure to antigens (39), the predominant expression of PD-1 within tumor cell nest-infiltrated T cells, particularly with T H 1 phenotypes, may be related to the abundance of tumor antigens in tumor cell nests and reduced intrinsic antitumor immunity. Considering that the presence of PD-1 + T cells correlates with favorable response to immune checkpoint blockade in melanoma, non-small cell lung cancer, and gastric cancer (17,20), the high frequency of PD-1 + helper T cells in tumor cell nests might be a potential therapeutic target by immune checkpoint blockade.…”

Naïve arthritogenic SKG T cells have a defect in anergy and a repertoire pruned by superantigen

“…T cell-intrinsic mechanisms that operate during thymic development (negative selection of selfreactive cells) and in peripheral T cells (functional unresponsiveness or 'anergy') are essential to maintain tolerance to self. Therefore, we sought to examine the expression of candidate genes known to be associated with these two tolerance programs (36)(37)(38)(39)(40)(41) in SKGNur and WTNur GFP hi cells compared to their GFP lo counterparts within the T.N4 Nr4a1 cluster, which had the highest expression of Nr4a1 and Nr4a3 (log2FC=4.0, adjusted P<1E-42) . We found that in the T.N4 Nr4a1 cluster, and in the overall dataset, GFP hi naïve CD4 T cells upregulated anergy and exhaustion-associated gene modules in both the WTNur and SKGNur subgroups (Fig.…”