CD4+ T cell anergy prevents autoimmunity and generates regulatory T cell precursors

Abstract

The role that anergy, an acquired state of T cell functional unresponsiveness, plays in natural peripheral tolerance remains unclear. In this study, we demonstrate that anergy is selectively induced in fetal antigen-specific maternal CD4+ T cells during pregnancy. A naturally occurring subpopulation of anergic polyclonal CD4+ T cells, enriched in self antigen-specific T cell receptors, is also observed in healthy hosts. Neuropilin-1 expression in anergic conventional CD4+ T cells is associated with thymic regulatory T cell (Treg cell)-related gene hypomethylation, and this correlates with their capacity to differentiate into Foxp3+ Treg cells that suppress immunopathology. Thus, our data suggest that not only is anergy induction important in preventing autoimmunity, but it also generates the precursors for peripheral Treg cell differentiation.

Ectopic Expression of Self-Antigen Drives Regulatory T Cell Development and Not Deletion of Autoimmune T Cells

“…In addition to Treg induction, self-antigen expression in periphery can also induce a state of non-responsiveness or anergy (50). Anergic T cells can be identified based on co-expression of folate-like receptor 4 (FR4) and CD73 (22).…”

High self-reactivity drives T-bet and potentiates Treg function in tissue-specific autoimmunity

“…Genomic DNA was isolated with a Zymo Research gDNA isolation kit (D4064) from male NOD.Foxp3 GFP splenic Tregs (top 35%) CD4 + GFP + CD5 hi and (bottom 35%) CD4 + GFP + C-D5 lo that were isolated by FACS. Primers for bisulfite sequencing were designed for Tnfrsf18 exon 5 (forward, 5′ -GAGGTGTAGTTGTTAGTTGAGGATGT -3′) (reverse, 5′ -AACCCCTACTCTCAC-CAAAAATATAA -3′), Ctla4 exon 2 (forward, 5′ -TGGTGTTGGTTAGTAGTTATGGTGT -3′) (reverse, 5′ -AAATTCCACCTTACAAAAATACAATC -3′), and Foxp3 intron 1 (forward, 5′ -GAG-GATTTGAATTGGATATGGTTTG -3′) (reverse, 5′ -CAACCTTAAACCCCTCTAACATC -3′), based on previously published primer sequences (41,72). Sodium bisulfite treatment of the extracted DNA was carried out with a Zymo Research EZ DNA Methylation kit (catalog 11-335).…”

Physiology and Pathology of Immune Dysregulation: Regulatory T Cells and Anergy

“…Treg cells, important for inducing and/or maintaining anergy and anergic T cells, can in turn alter their epigenetic and transcriptional programs to become Treg cells [151]. Anergic T cells may represent the intermediate reprogramming stage before they themselves become surveying Treg cells that maintain self-tolerance.…”

“…Anergic T cells may represent the intermediate reprogramming stage before they themselves become surveying Treg cells that maintain self-tolerance. T cell anergy and Treg induction are crucial mechanisms for reestablishing tolerance [152], and although presenting different phenotypic and functional characteristics, both mechanisms have in common the expression regulation of some genes, such as PD-1, ICOS, LAG3, CTLA-4, EGR2 [151], GRAIL [152,153], CBL-B,andITCH [154,155].…”