CD8+ T-cell memory: only the good ones last

doi:10.1016/j.coi.2004.05.004

Current Opinion in Immunology

Volume 16, Issue 4, August 2004, Pages 451-455

https://doi.org/10.1016/j.coi.2004.05.004 Get rights and content

Abstract

Generating long-lasting, protective CD8⁺ T-cell memory via vaccination is critical for combating infectious diseases. Advances in the past year have provided many new insights into how memory CD8⁺ T cells are generated. It is now recognized that CD8⁺ T cells differentiate from ‘effector memory’ cells into ‘central memory’ cells, which are stably maintained and confer superior protective immunity. Furthermore, CD4⁺ T-cell help plays an important role in guiding the differentiation of CD8⁺ T cells into long-lasting, functional memory. These findings have important implications for developing vaccine strategies that induce high-quality CD8⁺ T-cell memory, not just high quantity.

Introduction

CD8⁺ T cells are important for controlling threats to host survival that come from within, namely intracellularly replicating pathogens and cancerous growths. When a naı̈ve CD8⁺ T cell encounters a foreign antigen in the context of MHC class I (MHC-I), it divides and differentiates into many effector CD8⁺ T cells, which exert their immune function by direct cytolysis and secretion of cytokines, such as IFN-γ and TNF-α. This is followed by a programmed contraction that leaves a population of CD8⁺ memory T cells (T_M), which stably persists after resolution of the infection. Upon a second encounter with their specific antigen, CD8⁺ T_M rapidly divide, immediately exert effector functions and give rise to a large population of secondary effectors [1].

Memory — the ability of the immune system to respond with greater efficacy to a second insult by the same pathogen — has been recognized since antiquity and is a cardinal feature of the adaptive immune system. The ability to maintain this potential for an extended period of time is the hallmark of immunological memory and underpins the technology of vaccination. Our understanding of the molecular and cellular basis of immunological memory was first appreciated in B cells because the progressive changes in antibody production and maturation were the most accessible to analytical study. In recent years, however, technological advances have permitted a more detailed study of T-cell memory at the level of a single antigen-specific cell. This past year has been no exception. Here, we review the most significant contributions made to the study of CD8⁺ T_M during the past year.

Section snippets

CD8⁺ memory T cell subsets

It has long been known that humoral immune memory consists of two distinct populations: long-lived antibody-secreting plasma cells and memory B cells, which serve as a reservoir for the rapid generation of plasma cells [2]. The memory population of cellular immune cells, CD4⁺ and CD8⁺ T cells, may also be subdivided into two populations: effector memory T cells (T_EM) and central memory T cells (T_CM). These subsets were first described for CD4⁺ T cells on the basis of surface molecule

CD4⁺ T-cell help for CD8⁺ memory T-cell differentiation

CD4⁺ helper T cells (T_H) provide help for the CD8⁺ T-cell response to non-inflammatory antigens through the activation of antigen-presenting cells (APCs). However, the primary CD8⁺ T-cell response to most infectious agents is independent of CD4⁺ T_H. This is thought to result from the direct activation of APCs by infectious agents through Toll-like receptors and inflammatory signals that bypass the requirement for CD4⁺ T_H. It has also been shown that the secondary CD8⁺ T-cell response to viral

Delivery of CD4⁺ T-cell help for memory CD8⁺ T-cell differentiation

CD4⁺ T_H are delivered to B cells through direct CD40–CD40 ligand (CD40L) signaling between the B cells and CD4⁺ T cells [20]. CD4⁺ T-cell help for the primary CD8⁺ T-cell response has been shown to involve CD40–CD40L interactions between APCs and CD4⁺ T cells, leading to the APC activation required for the priming of naı̈ve CD8⁺ T cells 21., 22., 23.. More recently, Bourgeois et al. [13] suggested a new mechanism of CD4⁺ T-cell help for the CD8⁺ T-cell response that involves a direct CD40–CD40L

Conclusions

Advances in the past year have dramatically changed the way we think about the generation of CD8⁺ T_M. First, it has been shown that T_EM convert into T_CM and not vice versa, and, moreover, T_CM have a greater potential than T_EM for long-term stability and functional protection. Second, it has been demonstrated that CD4⁺ T_H are necessary during priming for the generation of stable and functional CD8⁺ T_M, suggesting that CD4⁺ T_H might play a role in the differentiation of T_CM. It remains to be

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

Acknowledgements

Thanks to Lauren Zenewicz for a critical reading of the manuscript.

References (28)

M.G McHeyzer-Williams et al.
B cell memory and the long-lived plasma cell
Curr Opin Immunol
(1999)
S.M Kaech et al.
Selective expression of the interleukin 7 receptor identifies effector CD8 T cells that give rise to long-lived memory cells
Nat Immunol
(2003)
H Ichii et al.
Role for Bcl-6 in the generation and maintenance of memory CD8+ T cells
Nat Immunol
(2002)
S.M Kaech et al.
Effector and memory T-cell differentiation: implications for vaccine development
Nat Rev Immunol
(2002)
F Sallusto et al.
Two subsets of memory T lymphocytes with distinct homing potentials and effector functions
Nature
(1999)
R.A Seder et al.
Similarities and differences in CD4+ and CD8+ effector and memory T cell generation
Nat Immunol
(2003)
D Masopust et al.
Preferential localization of effector memory cells in nonlymphoid tissue
Science
(2001)
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.
Lineage relationship and protective immunity of memory CD8 T cell subsets
Nat Immunol
(2003)
S.M Kaech et al.
Molecular and functional profiling of memory CD8 T cell differentiation
Cell
(2002)

M.G von Herrath et al.

CD4-deficient mice have reduced levels of memory cytotoxic T lymphocytes after immunization and show diminished resistance to subsequent virus challenge

J Virol

(1996)

J.M Riberdy et al.

Diminished primary and secondary influenza virus-specific CD8(+) T-cell responses in CD4-depleted Ig(−/−) mice

J Virol

(2000)

D.J Shedlock et al.

Role of CD4 T cell help and costimulation in CD8 T cell responses during Listeria monocytogenes infection

J Immunol

(2003)

C Bourgeois et al.

A role for CD40 expression on CD8+ T cells in the generation of CD8+ T cell memory

Science

(2002)

Cited by (46)

CD8 T Cell Memory to Pathogens
2016, Encyclopedia of Immunobiology
A key feature of the adaptive immune system is the ability of cytotoxic T lymphocytes (CTLs) to eliminate infected or diseased target cells in an antigen-specific manner, and then ‘remember’ the first encounter by way of long-lived memory CD8 T cells. Memory cells are capable of rapidly culling any future incursions owing to their heightened responsiveness and ready localization at portals of pathogen entry and sites of immune activation. Thus, understanding how memory CD8 T cells develop has been of long-standing interest to the field. This knowledge is not only significant for our vaccine development efforts aimed at inducing lifelong protective immunity, but also bears relevance to selectively potentiating effector CTLs during immunotherapy of cancer or chronic infections, or suppressing deleterious CTL functions during autoimmunity and transplantation. Here we review our current understanding of the mechanisms underlying the development and maintenance of robust CD8 T cell immunological memory that have emerged from the murine models of acute infections, and also discuss how some of these findings have been extended to humans. Recent discoveries in cellular and metabolic, transcriptional, and epigenetic control of memory with a diverse array of localization and functional properties are presented in the context of promising immunological interventions for treatment and vaccination.
Tight Regulation of Memory CD8<sup>+</sup> T Cells Limits Their Effectiveness during Sustained High Viral Load
2011, Immunity
Citation Excerpt :
Therefore, we next wanted to find a way to overcome the increased regulation of these cells and enhance memory cell persistence during chronic infection. Because CD4+ T cell help has been shown to be important for CD8+ T cell function during viral infections (Harty and Badovinac, 2008; Northrop and Shen, 2004; Wherry, 2011; Williams et al., 2006), we investigated whether increased LCMV-specific CD4+ T cell help could rescue the transferred memory cells during chronic infection. To answer this question, we cotransferred LCMV GP61 epitope-specific CD4+ T cells (Smarta) at the time of naive and memory CD8+ T cell cotransfer into normal CD4+ intact B6 mice.
To design successful vaccines for chronic diseases, an understanding of memory CD8⁺ T cell responses to persistent antigen restimulation is critical. However, most studies comparing memory and naive cell responses have been performed only in rapidly cleared acute infections. Herein, by comparing the responses of memory and naive CD8⁺ T cells to acute and chronic lymphocytic choriomeningitis virus infection, we show that memory cells dominated over naive cells and were protective when present in sufficient numbers to quickly reduce infection. In contrast, when infection was not rapidly reduced, because of high antigen load or persistence, memory cells were quickly lost, unlike naive cells. This loss of memory cells was due to a block in sustaining cell proliferation, selective regulation by the inhibitory receptor 2B4, and increased reliance on CD4⁺ T cell help. Thus, emphasizing the importance of designing vaccines that elicit effective CD4⁺ T cell help and rapidly control infection.
Immunology of Vaccines: Consideration of the Neonate as a Target for Vaccination
2009, Vaccines for Biodefense and Emerging and Neglected Diseases
Immunology of Vaccines: Consideration of the Neonate as a Target for Vaccination
2008, Vaccines for Biodefense and Emerging and Neglected Diseases
Heterogeneity and Cell-Fate Decisions in Effector and Memory CD8<sup>+</sup> T Cell Differentiation during Viral Infection
2007, Immunity
Citation Excerpt :
Although we are far from a complete understanding of these pathways, a substantial body of work has outlined some key factors, including (1) the role of CD4+ T cell help , (2) common gamma-chain cytokines, and (3) the strength of antigenic and inflammatory signals during T cell priming. CD4+ T cells, CD40-CD40L signals, and IL-2 help to maximize effector CD8+ T cell expansion, an effective E → M transition, and long-term maintenance after acute viral infections (Northrop and Shen, 2004; Rocha and Tanchot, 2004; Williams and Bevan, 2007). The result of defective CD4+ T cell help is the generation of a population of antiviral CD8+ T cells that largely resembles TEM cells, responds poorly to rechallenge, and in some cases expresses the death receptor, Trail (Badovinac et al., 2006; Janssen et al., 2005).
Heterogeneity is a hallmark of the adaptive immune system. This is most evident in the enormous diversity of B and T cell antigen receptors. There is also heterogeneity within antiviral T cell populations, and subsets of effector and memory T cells now permeate our thinking about specialization of T cell responses to pathogens. It has been less clear, however, how heterogeneity in developing virus-specific effector and memory T cells is related to cell-fate decisions in the immune response, such as the generation long-lived memory T cells. Here we discuss recent findings that might help redefine how heterogeneity in antiviral T cell populations gives rise to T cell subsets with short- and long-lived cell fates.
Humoral immune responses to the human immunodeficiency virus type-1 (HIV-1) in the genital tract compared to other mucosal sites (DOI:10.1016/j.jri.2006.05.006)
2007, Journal of Reproductive Immunology
Infection with the human immunodeficiency virus-1 (HIV-1) must be considered as a primarily mucosal disease. On a worldwide basis, the absolute majority of HIV infections occur through mucosal surfaces of the genital and intestinal tracts, and the earliest and most dramatic immunologic alterations are induced by the virus in mucosal tissues. However, individual compartments of mucosal components of the immune system display remarkable differences with respect to dominant antibody isotypes, virus phenotypes, densities and origins of cells involved in innate and specific immunity, presence or absence of inductive sites, and routes of immunizations that induce humoral and cellular responses. In this regard, the mucosal immune system of the female and male genital tracts exhibit several features which are distinct from other mucosal tissues, including dominance of the IgG isotype, local as well as pronounced systemic origin of antibodies, the absence of organized lymphoepithelial inductive sites and limited humoral responses stimulated by local antigen administration. Furthermore, it is evident that, irrespective of the route of infection, HIV-1 induces easily detectable IgG but not IgA specific antibody responses. These differences must be considered in the design of protective vaccines against infection with HIV and other agents of sexually transmitted diseases.

View all citing articles on Scopus

View full text

CD8+ T-cell memory: only the good ones last

Abstract

Introduction

Section snippets

CD8+ memory T cell subsets

CD4+ T-cell help for CD8+ memory T-cell differentiation

Delivery of CD4+ T-cell help for memory CD8+ T-cell differentiation

Conclusions

References and recommended reading

Acknowledgements

Curr Opin Immunol

Nat Immunol

Nat Immunol

Effector and memory T-cell differentiation: implications for vaccine development

Nat Rev Immunol

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

Nature

Similarities and differences in CD4+ and CD8+ effector and memory T cell generation

Nat Immunol

Preferential localization of effector memory cells in nonlymphoid tissue

Science

Priming of memory but not effector CD8 T cells by a killed bacterial vaccine

Science

Lineage relationship and protective immunity of memory CD8 T cell subsets

Nat Immunol

Molecular and functional profiling of memory CD8 T cell differentiation

Cell

CD4-deficient mice have reduced levels of memory cytotoxic T lymphocytes after immunization and show diminished resistance to subsequent virus challenge

J Virol

Diminished primary and secondary influenza virus-specific CD8(+) T-cell responses in CD4-depleted Ig(−/−) mice

J Virol

Role of CD4 T cell help and costimulation in CD8 T cell responses during Listeria monocytogenes infection

J Immunol

A role for CD40 expression on CD8+ T cells in the generation of CD8+ T cell memory

Science

CD8⁺ T-cell memory: only the good ones last

CD8⁺ memory T cell subsets

CD4⁺ T-cell help for CD8⁺ memory T-cell differentiation

Delivery of CD4⁺ T-cell help for memory CD8⁺ T-cell differentiation