Requirements for CD8 T-cell priming, memory generation and maintenance

doi:10.1016/j.coi.2007.04.010

Current Opinion in Immunology

Volume 19, Issue 3, June 2007, Pages 315-319

https://doi.org/10.1016/j.coi.2007.04.010 Get rights and content

Immunological memory is characterized by the ability to provide protection from secondary exposure to pathogens. CD8⁺ memory T cells provide protection from cell-associated antigens owing to their elevated frequency, rapid response and localization to sites of infection. Events occurring during primary exposure to antigen can impact not only the magnitude and quality of the initial cytotoxic T lymphocyte response but also the efficacy and longevity of the ensuing CD8⁺ memory pool. Recent advances shed light on the relative roles of TCR signals and environmental cues in guiding the development of CD8⁺ effector T cells into CD8⁺ memory T cells and supporting CD8⁺ memory T-cell maintenance.

Introduction

CD8⁺ T cells are part of the adaptive branch of the immune system and are key players in mediating immunity to intracellular pathogens and tumors. CD8⁺ T cells that carry the appropriate T-cell receptor (TCR) recognize antigen in the context of MHC class I. Encounter with antigen induces CD8⁺ T-cell activation and initiates a program of proliferation and differentiation into effector cytotoxic T lymphocytes (CTLs); this is known as the primary response. After the primary response peaks and antigen is cleared, most effector CD8⁺ T cells die, leaving behind a surviving fraction that persists as long-lived memory cells. Apart from their longevity, memory cells are further characterized by their ability to respond with enhanced efficacy to a second challenge with the same antigen (secondary response). These features plus their increased numbers allow memory CD8⁺ T cell to provide efficient long-lasting immunity against previously encountered pathogens.

What are the signals that promote the differentiation of effector and memory CD8⁺ T cells? In this article, we review recent insights concerning the impact of the various environmental cues that CD8⁺ T cells receive upon challenge with a pathogen and on the development of effector CTLs, long-lived memory and robust recall responses.

Section snippets

Priming of a naïve CD8 T cell

CD8⁺ T cells need various stimuli to become fully activated and induce differentiation and proliferation. These stimuli can be roughly divided into two categories: TCR signals and environmental cues, including but not limited to dendritic cell (DC) activation and costimulation, CD4 ‘help’, and soluble inflammatory and growth factors.

Stimulating a T cell through the TCR at physiologically relevant levels does not result in proper activation unless other environmental cues are present, such as

Generation of memory cells

A TCR signal does not dictate differentiation of a naïve CD8⁺ T cell all the way to a memory cell by itself. The necessity for signals in addition to the TCR is illustrated by the complex interplay of CD4⁺ T cells and cytokines with CD8⁺ T cells during the priming phase as well as the CD8⁺ T-cell memory maintenance phase.

It has been a long-standing belief that CD8⁺ T cells depend on CD4⁺ T-cell help for efficient priming and memory development [1]. Recent data show that CD8⁺ T cells can be

What are the signals that promote CD8⁺ memory T-cell differentiation?

There are at least two potential scenarios for the differential generation of end-stage effectors and memory precursors in vivo. In the first, memory precursors receive quantitatively different signals. In this scenario, increasing levels of stimulation caused by TCR–MHC interactions, growth and inflammatory factors, and costimulatory molecules could induce progressively more profound differentiation. Highly differentiated cells would move beyond the capacity to differentiate into memory cells

When do memory cells arise?

It is also uncertain how early memory CD8⁺ T cells arise after stimulation of a naïve CD8⁺ T cell. In one system, effector CD8⁺ T cells were shown to be refractory to further proliferation following restimulation [22], whereas Pamer's group observed memory-like cells as soon as five days post-infection as characterized by their ability to undergo further proliferation in response to secondary immunization [28]. In a more recent study, Harty and co-workers [29] used a similar prime boost

Maintenance of memory cells

Although it is likely that numerous factors promote the longevity and function of CD8⁺ memory T cells, IL-15, a member of the family of cytokines utilizing the common gamma chain receptor, has been the focus of numerous studies. CD8⁺ memory T cells depend on IL-15, as illustrated by the absence of memory-like cells in IL-15^−/− mice [30]. IL-15 is crucial for maintaining basal homeostatic turnover [31], and two recent reports show that IL-15–IL-15Rα complexes can induce vigorous CD8⁺ memory

Conclusions

Brief antigen stimulation can program CD8⁺ T cells to undergo many rounds of division and differentiation to effector and memory cells. Prolonged TCR stimulation is required for optimal accumulation of large numbers of effector CD8⁺ T cells, though other signals are involved as well. The complex interplay of environmental signals is illustrated by the recent discovery that CD8⁺ T cells that cannot respond to IL-2 have no pronounced defect during the primary response or the memory maintenance

References and recommended reading

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

• of special interest
•• of outstanding interest

References (35)

W.N. D'Souza et al.
Cutting edge: latecomer CD8 T cells are imprinted with a unique differentiation program
J Immunol
(2006)
G. Lauvau et al.
Priming of memory but not effector CD8 T cells by a killed bacterial vaccine
Science
(2001)
E.J. Wherry et al.
Antigen-independent memory CD8 T cells do not develop during chronic viral infection
Proc Natl Acad Sci USA
(2004)
M.J. Bevan
Helping the CD8⁺ T-cell response
Nat Rev Immunol
(2004)
J. Jiang et al.
Selective depletion of nonspecific T cells during the early stage of immune responses to infection
J Immunol
(2003)
R. Mercado et al.
Early programming of T cell populations responding to bacterial infection
J Immunol
(2000)
M.J. van Stipdonk et al.
Naïve CTLs require a single brief period of antigenic stimulation for clonal expansion and differentiation
Nat Immunol
(2001)
S.M. Kaech et al.
Memory CD8⁺ T cell differentiation: initial antigen encounter triggers a developmental program in naïve cells
Nat Immunol
(2001)
M. Prlic et al.
Duration of the initial TCR stimulus controls the magnitude but not functionality of the CD8⁺ T cell response
J Exp Med
(2006)
K. Tewari et al.
Differential requirement for Lck during primary and memory CD8⁺ T cell responses
Proc Natl Acad Sci USA
(2006)

T.R. Mempel et al.

T-cell priming by dendritic cells in lymph nodes occurs in three distinct phases

Nature

(2004)

M.A. Cannarile et al.

Transcriptional regulator Id2 mediates CD8⁺ T cell immunity

Nat Immunol

(2006)

P. Wong et al.

Feedback regulation of pathogen-specific T cell priming

Immunity

(2003)

M.A. Williams et al.

Developing and maintaining protective CD8⁺ memory T cells

Immunol Rev

(2006)

A.T. Stock et al.

Cutting edge: prolonged antigen presentation after herpes simplex virus-1 skin infection

J Immunol

(2004)

E.M. Janssen et al.

CD4⁺ T-cell help controls CD8⁺ T-cell memory via TRAIL-mediated activation-induced cell death

Nature

(2005)

J.C. Sun et al.

CD4⁺ T cells are required for the maintenance, not programming, of memory CD8⁺ T cells after acute infection

Nat Immunol

(2004)

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Requirements for CD8 T-cell priming, memory generation and maintenance

Introduction

Section snippets

Priming of a naïve CD8 T cell

Generation of memory cells

What are the signals that promote CD8+ memory T-cell differentiation?

When do memory cells arise?

Maintenance of memory cells

Conclusions

References and recommended reading

J Immunol

Science

Proc Natl Acad Sci USA

Helping the CD8+ T-cell response

Nat Rev Immunol

Selective depletion of nonspecific T cells during the early stage of immune responses to infection

J Immunol

Early programming of T cell populations responding to bacterial infection

J Immunol

Naïve CTLs require a single brief period of antigenic stimulation for clonal expansion and differentiation

Nat Immunol

Memory CD8+ T cell differentiation: initial antigen encounter triggers a developmental program in naïve cells

Nat Immunol

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

J Exp Med

Differential requirement for Lck during primary and memory CD8+ T cell responses

Proc Natl Acad Sci USA

T-cell priming by dendritic cells in lymph nodes occurs in three distinct phases

Nature

Transcriptional regulator Id2 mediates CD8+ T cell immunity

Nat Immunol

Feedback regulation of pathogen-specific T cell priming

Immunity

Developing and maintaining protective CD8+ memory T cells

Immunol Rev

Cutting edge: prolonged antigen presentation after herpes simplex virus-1 skin infection

J Immunol

CD4+ T-cell help controls CD8+ T-cell memory via TRAIL-mediated activation-induced cell death

Nature

CD4+ T cells are required for the maintenance, not programming, of memory CD8+ T cells after acute infection

Nat Immunol

What are the signals that promote CD8⁺ memory T-cell differentiation?

Helping the CD8⁺ T-cell response

Memory CD8⁺ T cell differentiation: initial antigen encounter triggers a developmental program in naïve cells

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

Differential requirement for Lck during primary and memory CD8⁺ T cell responses

Transcriptional regulator Id2 mediates CD8⁺ T cell immunity

Developing and maintaining protective CD8⁺ memory T cells

CD4⁺ T-cell help controls CD8⁺ T-cell memory via TRAIL-mediated activation-induced cell death

CD4⁺ T cells are required for the maintenance, not programming, of memory CD8⁺ T cells after acute infection