Lineage fate and intense debate: myths, models and mechanisms of CD4- versus CD8-lineage choice

Abstract

Following successful gene rearrangement at αβ T-cell receptor (TCR) loci, developing thymocytes express both CD4 and CD8 co-receptors and undergo a life-or-death selection event known as positive selection to identify cells expressing TCRs with potentially useful ligand specificities. Positively selected thymocytes must then decide whether to differentiate into CD4 + helper T cells or CD8 + cytotoxic T cells, a crucial decision known as CD4/CD8 lineage choice. This Review summarizes recent advances in our understanding of the cellular and molecular events involved in lineage fate decision and discusses them in the context of the major models of CD4/CD8 lineage choice.Throughout development, bipotential cells use environmental cues to determine cell fate, and elucidating the mechanisms by which they do so continues to be a fascinating area of investigation. An immunologically relevant example of bipotential cell-fate determination is the differentiation of CD4 + CD8 + (double positive, DP) thymocytes into either CD4 + helper T cells or CD8 + cytotoxic T cells. DP thymocytes are the first cells in the T-cell developmental pathway to express fully assembled αβ T-cell receptor (TCR) complexes on the cell surface ( Fig. 1), and it is the ligand specificity of their TCR that determines their subsequent developmental fate. αβTCRs are somatically generated transmembrane receptors with clonally unique structures that allow for a hugely diverse repertoire of recognition specificities. However, most thymocytes express αβTCRs that are incapable of engaging self MHC molecules and are therefore not useful to the host immune system. To eliminate cells expressing TCRs that cannot engage self MHC molecules, DP thymocytes are subjected to strict selection pressures in which cells bearing potentially useful TCR are the only ones signalled to survive and to continue their differentiation into functionally mature T cells. The vast majority of DP thymocytes do not receive TCR survival signals and undergo 'death by neglect' because their TCR cannot engage self MHC molecules. This life-or-death TCR mediated signalling event in DP thymocytes is referred to as 'positive selection' and results in the survival and maturation of cells bearing potentially useful TCRs.The success of positive selection in identifying potentially useful TCRs requires that DP thymocytes depend solely on signals downstream of TCR ligation for their survival, and that DP thymocytes be unresponsive to other survival signals. As a result, DP thymocytes are unique among T-lineage cells in that they are virtually refractory to the pro-survival cytokine interleukin-7 (IL-7), in part because DP thymocytes do not express receptors for IL-7 or most other pro-survival cytokines, and in part because DP thymocytes express high levels of SOCS1 (suppressor of cytokine signalling 1), a potent intracellular suppressor of cytokine signal transduction 1, 2 .Correspondence to A.S. e-mail: singera@mail.nih.gov. NIH Public Access Author ManuscriptNat Rev Immunol. Author manus...

The preTCR‐dependent DN3 to DP transition requires Notch signaling, is improved by CXCL12 signaling and is inhibited by IL‐7 signaling

“…At later time points, following the appearance of DP cells some CD4 high /CD8 low cells that did not proliferate upon TCR engagement could be recovered. These latter cells most likely represent the post-DP 'CD4 wannabes' described by Jameson and Bevan [45] or CD4 high /CD8 low 'intermediate' cells reviewed by Singer et al [46] that have not been TCR selected but have nevertheless down-modulated CD8 expression.…”

Differentiation of human thymic regulatory T cells at the double positive stage

“…DP cells bearing TCR-ab complexes able to engage self-MHC molecules are signaled to survive (positive selection) and to differentiate into functionally mature CD4 1 single positive (CD4SP; CD4 1 CD8 -CD3 high ) or CD8 1 single positive (CD8SP; CD4 -CD8 1 CD3 high ) T cells. Data from mouse models suggest that the strength and duration of TCR signaling drive the CD4 1 versus CD8 1 fate-decision during thymic differentiation, and the negative selection of cells with potentially auto-reactive TCRs [5]. TCR signaling has also been shown to be essential for Treg-cell differentiation in the thymus [6,7].…”

“…1A and B). The latter technical detail is relevant, as overestimation of FOXP3 1 DP cells in the murine thymus, due to doublet formation, has been described [22].It is known that DP cells may already be committed to either the CD4SP or CD8SP lineage, and have thus shut-down the synthesis of either CD4 or CD8, but still express both co-receptors at their surface [5,23]. Therefore, our first aim was to experimentally assess whether the FOXP3 1 DP population we detected in the human thymus were ''true'' DP cells.…”

Ubc9 Is Required for Positive Selection and Late-Stage Maturation of Thymocytes

“…Earlier stages of positive selection markers, such as upregulation of TCRb, CD5, and CD69, are strictly dependent on TCR-proximal signaling (8)(9)(10)(11). The engagement of TCR also induces coreceptor downregulation, pushing DP cells toward CD4 + CD8 int developmental intermediate stage, at which either CD4 or CD8 fate decisions are made (12). Positive selection also induces antiapoptotic BCL-2 protein, CCR7, and IL-7R expression.…”