The enigma of CD4-lineage specification

Abstract

CD4(+) T cells are essential for defenses against pathogens and affect the functions of most cells involved in the immune response. Although CD4(+) T cells generally recognize peptide antigens bound to MHC-II molecules, important subsets are restricted by other MHC or MHC-like molecules, including CD1d-restricted "invariant" iNK T cells. This review discusses recently identified nodes in the transcriptional circuits that are involved in controlling CD4(+) T-cell differentiation, notably the commitment factor Thpok and its interplay with Runx transcriptional regulators, and focuses on how transcription factors acting upstream of Thpok, including Gata3, Tox and E-box proteins, promote the emergence of CD4-lineage-specific gene expression patterns.

Figure 1. Transcription factors involved in CD4-lineage differentiation

Schematic depiction of the transcription factors involved in CD4-lineage differentiation. CD4-lineage genes are shown in red, CD8-lineage genes in blue. Arrows indicate positive (stimulatory) connections, ‘−‘ signs negative (inhibitory) connections. Plain lines indicate connections based on genetic evidence; in most cases, it remains to be determined whether the connection is through direct binding of the transcription factor to its target gene, or indirect. Dashed lines indicate connections inferred from the literature, but for which genetic support is missing or indirect. The ‘commitment’ loop between Runx3 and Thpok is highlight in purple. Runx3 inhibits Cd4 expression, and this activity is antagonized by Thpok. TCR signals in DP thymocytes promote the calcineurin dependent up-regulation of Tox and that, Erk-dependent, of Id3 (and possibly of the related factor Id2), that antagonize DNA binding by and transcriptional activity of E-proteins E2A and HEB. Continued TCR signals promote the up-regulation of Gata3, through pathways that remain to be elucidated but that involve Myb, and of Thpok, in a Gata3-dependent manner. Tox and E-proteins have antagonistic activities, suggesting that Tox and Id proteins have similar effects, or stimulate each other’s expression. E-proteins presumably prevent expression of Runx3, directly or not, as their inactivation results in the generation of CD8 cells even in the absence of TCR signaling [41]. Whether Eproteins also restrains the expression or activity of Thpok and Gata3 remains to be elucidated. See text for a detailed discussion.