Background/Purpose: T cell tolerance is essential for preventing autoimmune diseases and resolving inflammation. To maintain tolerance, CD4⁺ T cells recognizing self-antigens in the periphery can exert active suppression as regulatory T cells (Treg) or enter an inactive state known as anergy. Recent evidence suggests that anergy occurs naturally within a subpopulation of polyclonal CD4⁺ T cells and can generate precursors to Foxp3-expressing Treg cells. We aimed to identify transcription factors (TFs) underlying T cell anergy induction and its potential plasticity.

Methods: Polyclonal CD4⁺ T cell subsets from untreated C57BL/6 mice were sorted based on previously established markers for downstream sequencing-based interrogation. Anergic CD44^high Foxp3^– CD73^high FR4^high Nrp1⁺ T cells were compared to effector-memory (CD44^high Foxp3^– CD73^low FR4^low), Treg (Foxp3⁺ CD25⁺), and naïve (CD44^low) T cell populations. Divided aliquots from the same samples were processed in parallel to generate corresponding bulk RNA-seq and accessible chromatin DNA information. Bioinformatic analyses were applied to identify unique transcriptional networks in the anergic T cell subpopulation. Anergy-enriched TFs were then investigated in an antigen-specific system of tolerization by repeated peptide infusions.

Results: Paired epigenome and transcriptome analysis revealed a unique anergy signature driven by bZIP family (Batf, Cebpa, Nfil3, Maf), NFAT family (Nfatc1), and EGR family (Egr3) transcription factors. In response to peptide tolerization, antigen-specific CD4⁺ T cells from Batf-deficient mice demonstrated exaggerated expansion and minimal Foxp3⁺ Treg cell differentiation.

Conclusion: Our data indicate that a unique transcription factor network, including BATF, generates and maintains peripheral CD4⁺ T cell anergy.

Anergic T cells exhibit a distinct transcriptional program.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/epigenetic-and-transcriptional-programs-of-cd4-t-cell-anergy/