Heritable Gene Regulation in the CD4:CD8 T Cell Lineage Choice

Abstract

The adaptive immune system is dependent on functionally distinct lineages of T cell antigen receptor αβ-expressing T cells that differentiate from a common progenitor in the thymus. CD4 + CD8+ progenitor thymocytes undergo selection following interaction with MHC class I and class II molecules bearing peptide self-antigens, giving rise to CD8 + cytotoxic and CD4 + helper or regulatory T cell lineages, respectively. The strict correspondence of CD4 and CD8 expression with distinct cellular phenotypes has made their genes useful surrogates for investigating molecular mechanisms of lineage commitment. Studies of Cd4 and Cd8 transcriptional regulation have uncovered cis-regulatory elements that are critical for mediating epigenetic modifications at distinct stages of development to establish heritable transcriptional programs. In this review, we examine the epigenetic mechanisms involved in Cd4 and Cd8 gene regulation during T cell lineage specification and highlight the features that make this an attractive system for uncovering molecular mechanisms of heritability.

The cis-Regulatory Atlas of the Mouse Immune System

“…Several match known immunogenomics, but others were novel and unexpected. For example, many of the OCRs detected in the Cd8 locus correspond to (and help position) the enhancer elements mapped in classic studies of T cell differentiation (Issuree et al, 2017): some OCRs are active prior to transcription (E-8II), others only in mature CD8 + T cells (E8-VI) ( Figure 1B). We also identified previously unknown elements: Cd8 expression in DCs coincides with a novel OCR specific to CD8 + classic DCs (cDCs) and another solely active in plasmacytoid DCs (pDCs) ( Figure 1B).…”

“…As noted above, several of the OCRs at the Cd8 locus showed activity in the differentiation series prior to the appearance of Cd8a transcripts (i.e., E8-I and E8-II in DN3 and DN4). OCRs were also found at several known enhancer elements of Cd4, with the expected timing of activation (e.g., E4T, E4p, and E4D) (Issuree et al, 2017) ( Figure S4A). The S4 silencer was accessible in mature CD8 + T cells, indicating that silencing here is likely an ongoing process.…”

“…We then investigated more closely the changes in OCR activity that accompany T and B lymphocyte differentiation, attempting to track changes in regulatory elements that underlie these multistep cascades. At the two main cell-specific loci in the T lineage, Cd4 and Cd8, classic analyses have mapped a number of functionally important enhancer elements (Issuree et al, 2017). As noted above, several of the OCRs at the Cd8 locus showed activity in the differentiation series prior to the appearance of Cd8a transcripts (i.e., E8-I and E8-II in DN3 and DN4).…”

DNA (Hydroxy)Methylation in T Helper Lymphocytes

“…A representative example is provided by the CD4 gene, which during T cell development must be repressed in the CD8 + lineage of cytotoxic T cells and appropriately expressed in the CD4 + population of T helper lymphocytes. While cis and trans regulatory elements (enhancers and transcription factors) are crucial for the correct expression of the CD4 gene during development, mature T cells are much less sensitive to the perturbation of some of these regulatory elements, having epigenetically 'stabilized' CD4 expression at least in part through histone modifications [6]. Similarly, epigenetic changes occur during the process of T cell lineage commitment in the periphery, contributing to the polarization towards specific phenotypes [7].…”

NCOR1—a new player on the field of T cell development

“…During the selection process, TCR‐self‐peptide‐MHC signaling is supported by CD4 and CD8 through their function as coreceptors for MHC class II and MHC class I, respectively. For a detailed discussion of positive and negative selection as well as CD4/CD8 cell fate choice, we refer to several reviews that comprehensively summarize these topics. Collectively, these events result in the generation of CD4SP and CD8 SP thymocytes that, upon exiting the thymus, form the peripheral T cell pool with diverse specificities against a broad range of foreign antigens.…”