Strong tonic TCR signaling is associated with negative regulation of naive CD4+ T cells

Autor: Byron B Au-Yeung, Joel Eggert, Christopher Scharer, Wendy Zinzow-Kramer
Rok vydání: 2022
Předmět:
Zdroj: The Journal of Immunology. 208:167.12-167.12
ISSN: 1550-6606
0022-1767
DOI: 10.4049/jimmunol.208.supp.167.12
Popis: Naive T cells constantly experience tonic or basal TCR signals in response to self-peptides presented by MHC (pMHC) in vivo. We aimed to define how tonic TCR signaling impacts naive CD4+ T cells at the functional, transcriptional, and epigenetic levels. The transgenic Nur77-GFP reporter gene is responsive to tonic TCR signals. Naive CD4+ T cells can express a broad range of Nur77-GFP transgene expression at a single cell level, even if they express identical transgenic TCRs. Immature T cells that express high levels of Nur77-GFP following selection in the thymus tend to sustain high Nur77-GFP expression in the periphery. Naive CD4+ T cells with a Nur77-GFPHI Ly6C− phenotype experience the strongest tonic TCR signaling and in the OT-II TCR transgenic system, exhibit less sensitivity to stimulation with low doses of cognate pMHC or to weaker affinity pMHC. Analyses of gene expression in Nur77-GFPHI Ly6C− cells suggest a transcriptional program consistent with T cell activation, but also of negative regulation. Analyses of chromatin accessibility by ATAC-seq revealed over 3000 differentially accessible chromatin regions in Nur77-GFPHI Ly6C− cells, including several loci within or near genes encoding negative regulators such as Ctla-4 and Tim3. Nur77-GFPHI Ly6C− cells exhibited increased accessibility at multiple loci in the gene encoding Tox. A subset of these loci was previously reported to be more highly accessible in exhausted T cells. These findings suggest that persistent strong tonic TCR signaling may induce changes similar to those that occur during exhaustion. We propose that naive CD4+ T cells adapt to strong tonic TCR signaling and as a result, exhibit decreased sensitivity to subsequent TCR stimulations. Supported by a grant from NIH (K01AR065481)
Databáze: OpenAIRE
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