From the thymus to longevity in the periphery

doi:10.1016/j.coi.2010.03.003

Current Opinion in Immunology

Volume 22, Issue 3, June 2010, Pages 274-278

https://doi.org/10.1016/j.coi.2010.03.003 Get rights and content

An important attribute of the adaptive immune system is the ability to remember a prior encounter with a pathogen; an ability termed immunological memory. Bigger, better, and stronger responses are mounted upon a secondary encounter with the pathogen potentially resulting in clearance of the infection before the development of disease. We will review recent advances in the field of memory CD8⁺ T cell differentiation focusing on both intrinsic and extrinsic factors that govern the development of T cell memory.

Section snippets

Where it all begins

T cell development begins within the thymus from bone marrow derived progenitor cells and involves the acquisition of a T cell receptor (TCR) that fits with the allelic forms of the MHC molecules expressed in the individual. TCR diversity is vast arising from the imprecise random rearrangement of inherited gene segments for each chain. Before egress from the thymus the majority of cells that bear either self-reactive or non-functional TCR rearrangements are purged from the repertoire. Positive

New flavors of memory

Seminal work by Sallusto and Lanzavecchia introduced the concept that memory T cells are heterogeneous [16]. This was first observed in human blood, although the murine counterparts were discovered soon after. Central memory T cells circulate between secondary lymphoid organs, express the LN homing molecules CCR7 and CD62L, and do not exhibit immediate effector functions but can undergo significant recall proliferation upon antigen re-encounter. Effector memory T cells classically lack LN

Intrinsic factors that govern memory development

Two key transcription factors, T-bet and Eomesodermin (eomes), greatly influence memory CD8⁺ T cell development [27, 28]. How these transcription factors influence the T cell fate appears linked to their control of the expression of IL-7R and IL-15R [29, 28]. Signaling through these receptors is known to promote memory T cell survival and homoeostasis. Expression of these transcription factors is regulated by inflammatory cytokines, particularly IL-12. Elevated levels of IL-12 promote T-bet

Where do memory T cells come from?

A study by Stemberger et al. demonstrated that the fate of a naïve T cell is not predetermined before activation. Specifically they showed that daughters of a single cell could develop into both effector cells and memory T cells [36]. Whether memory T cells arise directly from naïve T cells or transition through an effector phase before adopting their memory status remains controversial. Currently there are two models to describe memory T cell development. The asymmetrical division model

Fading memories?

Every infection severe enough to engage an adaptive immune response alters the composition of the memory T cell pool. Pioneering work by Selin and Welsh demonstrated that subsequent heterologous infections induced the non-specific decay or attrition of pre-existing memory CD8⁺ T cells [44, 45]. It was proposed that over time, following infection by a plethora of pathogens, memory T cells specific for past infections are progressively diluted out by memory T cell populations directed against

Conclusion

Following activation a naïve T cell has two fates — become a senescent effector and die or differentiate into a memory T cell and live. When does this fate decision happen during an immune response and what are the extrinsic and intrinsic factors that govern this decision remain important issues.

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

• of special interest
•• of outstanding interest

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However, some lymphocytes can survive this contraction phase and become the memory pool of lymphocytes. These cells respond rapidly and effectively to reinfection (Wakim & Bevan, 2010). The pool of memory T cells generated following infection are heterogeneous, with functionally distinct subsets of memory T cell described based upon their expression of costimulatory and adhesion molecules (Sallusto, Lenig, Forster, Lipp, & Lanzavecchia, 1999).
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View full text

From the thymus to longevity in the periphery

Section snippets

Where it all begins

New flavors of memory

Intrinsic factors that govern memory development

Where do memory T cells come from?

Fading memories?

Conclusion

References and recommended reading

Curr Opin Immunol

Curr Opin Immunol

Mol Immunol

Nat Immunol

Immunity

Proc Natl Acad Sci U S A

Immunity

Science

Immunity

Nat Immunol

Science

Nat Immunol

Science

Thymic output in aged mice

Proc Natl Acad Sci U S A

Fibroblastic reticular cells in lymph nodes regulate the homeostasis of naive T cells

Nat Immunol

The induction of virus-specific CTL as a function of increasing epitope expression: responses rise steadily until excessively high levels of epitope are attained

J Immunol

Duration of the initial TCR stimulus controls the magnitude but not functionality of the CD8+ T cell response

J Exp Med

Complete but curtailed T-cell response to very low-affinity antigen

Nature

Vaccine adjuvants alter TCR-based selection thresholds

Immunity

Therapeutic use of IL-2 to enhance antiviral T-cell responses in vivo

Nat Med

IL-15 regulates CD8+ T cell contraction during primary infection

J Immunol

Macrophage- and dendritic-cell-derived interleukin-15 receptor alpha supports homeostasis of distinct CD8+ T cell subsets

Immunity

Two subsets of memory T lymphocytes with distinct homing potentials and effector functions

Nature

Duration of the initial TCR stimulus controls the magnitude but not functionality of the CD8⁺ T cell response

IL-15 regulates CD8⁺ T cell contraction during primary infection

Macrophage- and dendritic-cell-derived interleukin-15 receptor alpha supports homeostasis of distinct CD8⁺ T cell subsets