T cell lineage commitment: identity and renunciation

Abstract

Precursors undertaking T cell development shed their access to other pathways in a sequential process that begins before entry into the thymus and continues through many cell cycles afterward. This process involves three levels of regulatory change, in which the cells' intrinsic transcriptional regulatory factors, expression of signaling receptors (e.g., Notch1), and expression of distinct homing receptors separately contribute to confirmation of T cell identity. Each alternative potential has a different underlying molecular basis that is neutralized and then permanently silenced through different mechanisms in early T cell precursors. This regulatory mosaic has notable implications for the hierarchy of relationships linking T lymphocytes to other hematopoietic fates.

Figure 1. Exclusion of different hematopoietic fate alternatives on the approach to T-cell identity

The figure shows the changes in developmental potential described in the text, in the context of a likely sequence of hematopoietic precursors from bone marrow to thymic entry (vertical dashed line) through T-lineage commitment. Graphs below the stages shown represent levels of potential remaining at each stage for erythroid, myeloid/DC, B, and NK pathway alternative. In each case, “potential” is defined as an ability of a normal, unmodified cell to differentiate to a given fate when the cell is simply transferred to a permissive microenvironment. The uncertainty about different precursor types that may seed the thymus is shown as dual paths leading to thymic entry. A dip in “T cell potential” below the CLPs represents a subset of CLPs with reduced but detectable T cell potential. The apparent conditional decrease in myeloid potential seen for many prethymic precursors when assayed in vivo is depicted as a partial decrease of myeloid potential before the thymus, followed by a plateau of continuing potential until this fate is excluded by cell-intrinsic mechanisms at a later stage within the thymus. Cell types: HSC, hematopoietic stem cell; MPP, multipotent precursor; LMPP, lymphoid-primed multipotent precursor; ELP, early lymphoid precursor; CLP, common lymphoid precursor; DN1/ETP, c-Kit⁺⁺ CD44⁺ CD25^- DN cells (CD4^- CD8^- TCR^- Lin^- early T cells); DN2a, c-Kit⁺⁺ CD44⁺ CD25⁺ DN cells; DN2b, c-Kit⁺ CD44⁺ CD25⁺ DN cells; DN3a, c-Kit^low CD44^low CD25⁺ DN cells; DN3b, c-Kit^low CD44^low CD25⁺ DN cells undergoing CD27 and CD28 upregulation and size increase triggered by β-selection. Later stages of αβ T cell development, not shown, include differentiation to CD4⁺ CD8⁺ cells after β-selection followed by selection of a few chosen survivors into CD4⁺ or CD8⁺ fates.