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  • Review Article
  • Published:

Naive T cell homeostasis: from awareness of space to a sense of place

Key Points

  • Maintenance of the naive T cell pool is not a default state but is dependent on constant stimulation of naive T cells by extrinsic factors.

  • Recognition of self-peptide–MHC complexes through the T cell receptor provides a signal for naive T cell survival. This signal also affects multiple aspects of T cell function, including antigen reactivity and migration.

  • Interleukin-7 (IL-7) has a central role in supporting T cell survival, proliferation and migration through Janus kinase (JAK)–signal transducer and activator of transcription (STAT) and phosphoinositide 3-kinase (PI3K)–AKT signalling pathways.

  • Responsiveness to IL-7 is dictated by the expression levels of IL-7 receptor-α (IL-7Rα), and this expression is regulated by a negative feedback loop following receptor engagement. Such tight control is crucial for T cell homeostasis.

  • Continuous interaction with the stromal cell network in secondary lymphoid organs is crucial for naive T cells to optimally encounter and respond to homeostatic factors.

Abstract

The peripheral naive T cell pool is fairly stable in number, diversity and functional competence in the absence of vigorous immune responses. However, this apparent tranquillity is not an intrinsic property of T cells but involves continuous tuning of the T cell pool composition by homeostatic signals. In the past decade, studies have revealed that naive T cells rely on combinatorial signals from self-peptide–MHC complexes and interleukin-7 for their physical and functional maintenance. Competition for these factors dictates T cell 'space'. In addition, recent studies show that these and other homeostatic factors are offered to T cells on stromal cell networks, which also serve to guide T cell trafficking in secondary lymphoid organs. Such findings suggest the importance of 'place' in the perception and integration of homeostatic cues for the maintenance and functional tuning of the naive T cell pool.

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Figure 1: Fighting for a niche.
Figure 2: Sharing homeostatic needs with interleukin-7 receptor signalling.
Figure 3: Moving to stay the same: access to homeostatic cues during T cell trafficking.

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Acknowledgements

We thank the members of the Jameson and Hogquist laboratories for suggestions and comments. This work was supported by grants from the NIH (S.C.J.) and Japan Society for the Promotion of Science (K.T.).

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Glossary

Lymphopenic mice

Mice that have lost both B and T cells, for example severe combined immunodeficient or recombinase activing gene-deficient mice, which lack an enzyme required for the generation of B and T cell receptors, or lost only T cells, for example, in nu/nu mice, which lack a thymus.

Positive selection

A step in the process of T cell differentiation in the thymus that selects double-positive CD4+CD8+ T cells for survival and maturation, based on the appropriate degree of interaction between their T cell receptor and self-peptide–MHC complexes expressed by thymic epithelial cells. Depending on the class of MHC molecule recognized, thymocytes are positively selected either to a CD4 or a CD8 single-positive T cell fate.

Mammalian target of rapamycin

(mTOR). A conserved serine/threonine protein kinase that regulates cell growth and metabolism, as well as cytokine and growth-factor expression, in response to environmental cues. mTOR receives stimulatory signals from RAS and phosphoinositide 3-kinase downstream of growth factors, as well as nutrients, such as amino acids, glucose and oxygen.

Multiple sclerosis

A neurological disease that is characterized by focal demyelination in the central nervous system with lymphocytic infiltration.

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Takada, K., Jameson, S. Naive T cell homeostasis: from awareness of space to a sense of place. Nat Rev Immunol 9, 823–832 (2009). https://doi.org/10.1038/nri2657

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