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  • Review Article
  • Published:

Signal integration and crosstalk during thymocyte migration and emigration

Key Points

  • T cell development requires the migration of haematopoietic progenitors from the bone marrow to the thymus.

  • T cell lineage potential is broadly distributed among primitive bone marrow-derived progenitor populations. However, the ability to migrate to the thymus is tightly regulated.

  • Thymic homing has a molecular basis that is beginning to be understood. Known molecules implicated in thymic homing include P-selectin glycoprotein ligand 1 and the chemokine receptors CCR7 and CCR9.

  • Migration of developing thymocytes through different regions of the thymus is crucial for normal T cell development and is regulated by multiple chemokine receptors, including CXCR4, CCR7 and CCR9. Crosstalk between these receptors and developmental receptors (the T cell receptor (TCR) and pre-TCR) regulates both thymocyte migration and thymocyte development.

  • Thymocyte emigration is precisely timed to occur only after maturation is completed and after thymocytes are screened by negative selection to remove overtly autoreactive cells. The chemotactic receptor sphingosine-1-phosphate receptor 1 (S1P1; encoded by S1PR1) has a crucial role in regulating thymocyte export.

  • Current data suggest a model for thymocyte emigration in which TCR signalling controls the timing of export by regulating the expression of S1P1 and CCR7, as well as that of CD69, which functions to downregulate S1P1 surface expression. TCR signals inhibit S1pr1 transcription and upregulate CD69, thereby preventing thymocyte export. Cessation of TCR signalling induces S1pr1 transcription and downregulates CD69, rendering thymocytes susceptible to S1P1-mediated signalling and promoting thymocyte emigration.

Abstract

The thymus produces self-tolerant functionally competent T cells. This process involves the import of multipotent haematopoietic progenitors that are then signalled to adopt the T cell fate. Expression of T cell-specific genes, including those encoding the T cell receptor (TCR), is followed by positive and negative selection and the eventual export of mature T cells. Significant progress has been made in elucidating the signals that direct progenitor cell trafficking to, within and out of the thymus. These advances are the subject of this Review, with a particular focus on the role of reciprocal cooperative and regulatory interactions between TCR- and chemokine receptor-mediated signalling.

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Figure 1: An overview of regulated migration events during T cell development.
Figure 2: A model for the regulation of CD4 SP and CD8 SP thymocyte export by TCR signalling.

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Acknowledgements

The authors thank Y. Takahama, J. C. Zúñiga-Pflücker, D. A. Zlotoff, S. Zhang, R. Lesourne, L. Li and K. Pfeifer for critical reading of and helpful suggestions on the manuscript. A.B. was supported by US National Institutes of Health grants AI059621 and RC1HL099758, and a Scholar Award from the Leukemia and Lymphoma Society.

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Glossary

G protein-coupled receptors

(GPCRs). A family of receptors that are each composed of seven membrane-spanning helical segments. These receptors associate with heterotrimeric G proteins, which are a family of intracellular signalling proteins that have common β- and γ-chains, and one of several α-chains. The α-chain determines the nature of the signal that is transmitted from a ligand-occupied GPCR to downstream effector systems.

pre-TCR

A receptor that is expressed on pre-T cells. It is formed by a T cell receptor (TCR) β-chain paired with a surrogate TCR α-chain (known as the invariant pre-Tα protein). The receptor complex includes CD3 proteins and transduces signals that allow further T cell development.

LSK cells

A mouse cell population that is defined by the expression of stem cell antigen 1 (SCA1) and the receptor for stem cell factor, KIT, and the absence of lineage or maturation markers (LIN). This is a heterogeneous population that contains multipotent progenitors and true self-renewing stem cells and is highly enriched in HSCs.

Double negative cells

(DN cells).The most immature thymocytes lack expression of the co-receptors CD4 and CD8, and are referred to as DN cells. This compartment can be further subdivided on the basis of CD44 and CD25 expression into four subpopulations: DN1 (CD25CD44+), DN2 (CD25+CD44+), DN3 (CD25+CD44) and DN4 (CD25CD44).

Notch

A transmembrane receptor involved in the pathway for direct cell–cell signalling through its association with a transmembrane ligand of the Delta or Serrate (jagged) family on a neighbouring cell.

β-selection

The controlled developmental transition beyond the double negative 3 (DN3) stage to the double positive stage that is limited to T cells that have successfully rearranged their T cell receptor (TCR) β-chain genes to express a functional pre-TCR on the cell surface. The conditional developmental arrest encountered at the DN3 stage is termed the 'β-selection checkpoint'.

Two-photon laser scanning microscopy

Laser scanning microscopy that uses pulsed infrared laser light for the excitation of conventional fluorophores or fluorescent proteins. This technique greatly reduces photodamage of living specimens and improves the depth of tissue penetration, owing to the low level of light scattering within the tissue.

Positive selection

The maturation of immature CD4+CD8+ precursor thymocytes induced by T cell receptor (TCR) signals that result from binding to self peptide–MHC ligands on thymic epithelial cells. This process selects thymocytes that express TCRs that are able to interact with self MHC molecules.

Negative selection

T cells that express T cell receptors with high affinity for self antigens are eliminated from the repertoire by apoptosis after recognition of their target antigen presented by medullary thymic epithelial or dendritic cells.

Thymic epithelial cells

(TECs). Medullary TECs and cortical TECs are phenotypically and functionally distinctive, providing specialized niches necessary for the stage-specific development of thymocytes migrating through these zones.

14-3-3

A family of conserved proteins present in all eukaryotic organisms that are involved in such diverse cellular processes as apoptosis and stress, as well as intracellular signalling and cell cycle regulation. 14-3-3 proteins function as adaptors in protein interactions and can regulate protein localization and enzymatic activity. Approximately 100 binding partners for the 14-3-3 proteins have been reported.

Lmo2-transgenic mice

Transgenic mice that overexpress Lmo2 (also known as rhombotin 2) in immature thymocytes. Adult Lmo2-transgenic mice develop thymocyte tumours (that is, T cell acute lymphoblastic leukaemia (T-ALL)).

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Love, P., Bhandoola, A. Signal integration and crosstalk during thymocyte migration and emigration. Nat Rev Immunol 11, 469–477 (2011). https://doi.org/10.1038/nri2989

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