Heterogeneity of CD4+ and CD8+ T cells

doi:10.1016/S0952-7915(03)00037-2

Current Opinion in Immunology

Volume 15, Issue 3, June 2003, Pages 336-342

https://doi.org/10.1016/S0952-7915(03)00037-2 Get rights and content

Abstract

There is extensive plasticity in the T-cell response to antigen. Helper CD4⁺ T cells, cytotoxic CD8⁺ T cells, the progression from naı̈ve to effector and memory T cells, and differentiation into Th1, Tc1, Th2 and Tc2 subsets have long been recognized. More recently it has become apparent that T-cell populations display additional diversity in terms of phenotype, anatomical distribution and effector function.

Introduction

T cells display extensive diversity in terms of phenotype, function and anatomical distribution. In general, naı̈ve T cells represent the most homogeneous pool of T cells, as they lack most effector functions. However, activation through the T-cell receptor (TCR) results in proliferation and the acquisition of a variety of effector functions that ultimately produce an array of effector and memory cell types. These cells differ in their capacity to proliferate in response to antigen, mediate cytotoxic responses, and execute regulatory functions. Some of these differences can be attributed to distinct developmental programs and others may be related to issues of antigen persistence and anatomical distribution of cells. Critical questions raised by these observations are: what are the underlying mechanisms of T-cell heterogeneity? and, what is the relevance of this to the control of infections and tumors?

Section snippets

Functional heterogeneity in the immune system

The most-studied differences between T-cell subsets are the distinct panels of cytokines expressed by CD4⁺ T helper 1 (Th1; type 1) and Th2 (type 2) cells upon activation 1., 2.. Th1 cells classically produce the signature cytokine IFN-γ, whereas Th2 cells produce IL-4 and IL-5. The initial findings were with CD4⁺ T cell subsets but other studies have also identified a role for effector CD8⁺ T cell subsets 3., 4., as both CD8⁺ type 1 (Tc1) and CD8⁺ type 2 (Tc2) cytokine patterns are initiated

Heterogeneity in the functions of memory T cells

Recently, it has emerged that subpopulations of resting memory T cells exhibit heterogeneity in the expression of effector functions. Whereas resting memory T cells in secondary lymphoid organs are generally not cytolytic, those in peripheral organs express immediate cytolytic activity ex vivo that can be detected in a four hour chromium release assay 43.••, 44.. For example, studies by Masopust and colleagues [43^••] showed that, following vesicular stomatitis virus infection, memory T cells

Understanding T-cell heterogeneity

The first question in understanding T-cell heterogeneity is: does heterogeneity reflect different lineages or merely different stages in a linear differentiation pathway? In the case of CD4⁺ and CD8⁺ T cells, the two populations clearly represent distinct lineages of cells that diverge from one another in the thymus. They are distinguished by different functions and express different lineage specific markers. Their differing functions include class-specific MHC-restricted recognition of

Conclusions

It has become increasingly apparent that T-cell populations are heterogeneous in terms of phenotype, function and distribution. In some cases, T-cell heterogeneity reflects distinct lineages of cells that are established independently of antigen challenge, such as the development of CD4⁺ and CD8⁺ T cells. In other cases, the heterogeneity appears to be due to differential T-cell responses to antigen stimulation. Some of these activation-related differences clearly represent divergent pathways,

Update

Ahmed and his colleagues [87] have addressed the issue of whether CCR7, CD62L^high central memory cells and CCR7, CD62L^low effector memory cells represent different lineages (as some have proposed) or represent different stages in a linear pathway. They conclude that effector memory cells give rise to central memory in a linear pathway. This contrasts with the model espoused by Lanzavecchia and colleagues 88., 89., in which effector memory cells arise from central memory cells. Yet a third point

References and recommended reading

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

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of special interest
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of outstanding interest

Acknowledgements

The work described in this review was supported by National Institutes of Health grants R01 HL69502 (DLW), P01 HL-63925 (DLW and RWD), P01 AI 46530 (RWD) and R01 CA 71833 (RWD. We thank Susan Swain, Roslyn Kemp, Linda Cauley and Marcy Blackman for critically reviewing the manuscript.

References (92)

S.L Swain
T-cell subsets. Who does the polarizing?
Curr. Biol.
(1995)
T.R Mosmann et al.
Functions of CD8 T-cell subsets secreting different cytokine patterns
Semin. Immunol.
(1997)
R Falchetti et al.
Splenic CD4⁺ and CD8⁺ T cells from influenza immune mice concurrently produce in vitro IL2, IL4, and IFN-gamma
Cell Immunol.
(1996)
A.H Thompson et al.
Heterogeneous cytokine production by acutely stimulated bronchoalveolar T lymphocytes in reovirus 1/Lang-infected mice
Cell Immunol.
(1999)
P.P Lee et al.
Characterization of circulating T cells specific for tumor-associated antigens in melanoma patients
Nat. Med.
(1999)
C.A Blish et al.
Anergic CD8⁺ T cells can persist and function in vivo
J. Immunol.
(1999)
L Lefrancois
Dual personality of memory T cells
Trends Immunol.
(2002)
E Roman et al.
CD4 effector T cell subsets in the response to Influenza: heterogeniety, migration, and function
J. Exp. Med.
(2002)
D.J Campbell et al.
Intestinal attraction: CCL25 functions in effector lymphocyte recruitment to the small intestine
J. Clin. Invest
(2002)
S Fecteau et al.
CTLA-4 up-regulation plays a role in tolerance mediated by CD45
Nat. Immunol.
(2001)

H Sepulveda et al.

CD28, IL-2-independent costimulatory pathways for CD8 T lymphocyte activation

J. Immunol.

(1999)

E.L Tham et al.

The poststimulation program of CD4 versus CD8 T cells (death versus activation-induced nonresponsiveness)

J. Immunol.

(2002)

E Vivier et al.

Lymphocyte activation via NKG2D: towards a new paradigm in immune recognition?

Curr. Opin. Immunol.

(2002)

H Groux et al.

A CD4⁺ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis

Nature

(1997)

E.M Janssen et al.

CD4(+) T cells are required for secondary expansion and memory in CD8(+) T lymphocytes

Nature

(2003)

A.K Abbas et al.

Functional diversity of helper T lymphocytes

Nature

(1996)

A Cerwenka et al.

In vivo persistence of CD8 polarized T cell subsets producing type 1 or type 2 cytokines

J. Immunol.

(1998)

A Cerwenka et al.

Migration kinetics and final destination of type 1 and type 2 CD8 effector cells predict protection against pulmonary virus infection

J. Exp. Med.

(1999)

N Baumgarth et al.

Novel features of the respiratory tract T-cell response to influenza virus infection: lung T cells increase expression of gamma interferon mRNA in vivo and maintain high levels of mRNA expression for interleukin-5 (IL-5) and IL-10

J. Virol.

(1994)

R.A Seder et al.

Acquisition of lymphokine-producing phenotype by CD4⁺ T cells

Annu. Rev. Immunol.

(1994)

A.L Wurster et al.

Interleukin 21 is a T helper (Th) cell 2 cytokine that specifically inhibits the differentiation of naive Th cells into interferon gamma-producing Th1 cells

J. Exp. Med.

(2002)

R.B Smeltz et al.

Role of IFN-gamma in Th1 differentiation: IFN-gamma regulates IL-18R alpha expression by preventing the negative effects of IL-4 and by inducing/maintaining IL-12 receptor beta 2 expression

J. Immunol.

(2002)

S.L Swain

Interleukin 18: tipping the balance towards a T helper cell 1 response

J. Exp. Med.

(2001)

Y Zhang et al.

Interferon gamma stabilizes the T helper cell type 1 phenotype

J. Exp. Med.

(2001)

X Wang et al.

In vivo priming of CD4 T cells that produce interleukin (IL)-2 but not IL-4 or interferon (IFN)-gamma, and can subsequently differentiate into IL-4- or IFN-gamma-secreting cells

J. Exp. Med.

(2001)

M Ahmadzadeh et al.

Functional plasticity of an antigen-specific memory CD4 T cell population

Proc. Natl. Acad. Sci. U.S.A.

(2002)

M.K Slifka et al.

Activated and memory CD8⁺ T cells can be distinguished by their cytokine profiles and phenotypic markers

J. Immunol.

(2000)

J.K Sandberg et al.

Functional heterogeneity of cytokines and cytolytic effector molecules in human CD8⁺ T lymphocytes

J. Immunol.

(2001)

A Kelso et al.

Single-cell analysis by RT-PCR reveals differential expression of multiple type 1 and 2 cytokine genes among cells within polarized CD4⁺ T cell populations

Int. Immunol.

(1999)

C.Y Wu et al.

Distinct lineages of T(H)1 cells have differential capacities for memory cell generation in vivo

Nat. Immunol.

(2002)

D.J Campbell et al.

Separable effector T cell populations specialized for B cell help or tissue inflammation

Nat. Immunol.

(2001)

M.A Suni et al.

CD4(+)CD8(dim) T lymphocytes exhibit enhanced cytokine expression, proliferation and cytotoxic activity in response to HCMV and HIV-1 antigens

Eur. J. Immunol.

(2001)

V Appay et al.

Characterization of CD4⁺ CTLs ex vivo

J. Immunol.

(2002)

V Appay et al.

HIV-specific CD8⁺ T cells produce antiviral cytokines but are impaired in cytolytic function

J. Exp. Med.

(2000)

J Lieberman et al.

Dressed to kill? A review of why antiviral CD8 T lymphocytes fail to prevent progressive immunodeficiency in HIV-1 infection

Blood

(2001)

J.M Moser et al.

Antiviral CD8⁺ T cell responses in neonatal mice: susceptibility to polyoma virus-induced tumors is associated with lack of cytotoxic function by viral antigen-specific T cells

J. Exp. Med.

(2001)

A.J Zajac et al.

Viral immune evasion due to persistence of activated T cells without effector function

J. Exp. Med.

(1998)

R.A Nazaruk et al.

Functional diversity of the CD8⁺ T-cell response to Epstein-Barr virus (EBV): implications for the pathogenesis of EBV-associated lymphoproliferative disorders

Blood

(1998)

J.D Powell et al.

Molecular regulation of interleukin-2 expression by CD28 co-stimulation and anergy

Immunol. Rev.

(1998)

E.J Usherwood et al.

Functionally heterogeneous CD8⁺ T-cell memory is induced by Sendai virus infection of mice

J. Virol.

(1999)

M Ahmadzadeh et al.

Heterogeneity of the memory CD4 T cell response: persisting effectors and resting memory T cells

J. Immunol.

(2001)

J Hernandez et al.

Uncoupling of proliferative potential and gain of effector function by CD8⁺ T cells responding to self-antigens

J. Exp. Med.

(2002)

J Hernandez et al.

Phenotypic and functional analysis of CD8⁺ T cells undergoing peripheral deletion in response to cross-presentation of self-antigen

J. Exp. Med.

(2001)

U Blohm et al.

Lack of effector cell function and altered tetramer binding of tumor-infiltrating lymphocytes

J. Immunol.

(2002)

D.J Nelson et al.

Tumor progression despite efficient tumor antigen cross-presentation and effective ‘arming’ of tumor antigen-specific CTL

J. Immunol.

(2001)

M Gonzalez et al.

The balance between donor T cell anergy and suppression versus lethal graft-versus-host disease is determined by host conditioning

J. Immunol.

(2002)

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Heterogeneity of CD4+ and CD8+ T cells

Abstract

Introduction

Section snippets

Functional heterogeneity in the immune system

Heterogeneity in the functions of memory T cells

Understanding T-cell heterogeneity

Conclusions

Update

References and recommended reading

Acknowledgements

Curr. Biol.

Semin. Immunol.

Cell Immunol.

Cell Immunol.

Nat. Med.

J. Immunol.

Trends Immunol.

J. Exp. Med.

J. Clin. Invest

Nat. Immunol.

J. Immunol.

J. Immunol.

Curr. Opin. Immunol.

Nature

Nature

Functional diversity of helper T lymphocytes

Nature

In vivo persistence of CD8 polarized T cell subsets producing type 1 or type 2 cytokines

J. Immunol.

Migration kinetics and final destination of type 1 and type 2 CD8 effector cells predict protection against pulmonary virus infection

J. Exp. Med.

Novel features of the respiratory tract T-cell response to influenza virus infection: lung T cells increase expression of gamma interferon mRNA in vivo and maintain high levels of mRNA expression for interleukin-5 (IL-5) and IL-10

J. Virol.

Acquisition of lymphokine-producing phenotype by CD4+ T cells

Annu. Rev. Immunol.

Interleukin 21 is a T helper (Th) cell 2 cytokine that specifically inhibits the differentiation of naive Th cells into interferon gamma-producing Th1 cells

J. Exp. Med.

Role of IFN-gamma in Th1 differentiation: IFN-gamma regulates IL-18R alpha expression by preventing the negative effects of IL-4 and by inducing/maintaining IL-12 receptor beta 2 expression

J. Immunol.

Interleukin 18: tipping the balance towards a T helper cell 1 response

J. Exp. Med.

Interferon gamma stabilizes the T helper cell type 1 phenotype

J. Exp. Med.

In vivo priming of CD4 T cells that produce interleukin (IL)-2 but not IL-4 or interferon (IFN)-gamma, and can subsequently differentiate into IL-4- or IFN-gamma-secreting cells

J. Exp. Med.

Functional plasticity of an antigen-specific memory CD4 T cell population

Proc. Natl. Acad. Sci. U.S.A.

Activated and memory CD8+ T cells can be distinguished by their cytokine profiles and phenotypic markers

J. Immunol.

Functional heterogeneity of cytokines and cytolytic effector molecules in human CD8+ T lymphocytes

J. Immunol.

Single-cell analysis by RT-PCR reveals differential expression of multiple type 1 and 2 cytokine genes among cells within polarized CD4+ T cell populations

Int. Immunol.

Distinct lineages of T(H)1 cells have differential capacities for memory cell generation in vivo

Nat. Immunol.

Separable effector T cell populations specialized for B cell help or tissue inflammation

Nat. Immunol.

CD4(+)CD8(dim) T lymphocytes exhibit enhanced cytokine expression, proliferation and cytotoxic activity in response to HCMV and HIV-1 antigens

Eur. J. Immunol.

Characterization of CD4+ CTLs ex vivo

J. Immunol.

HIV-specific CD8+ T cells produce antiviral cytokines but are impaired in cytolytic function

J. Exp. Med.

Dressed to kill? A review of why antiviral CD8 T lymphocytes fail to prevent progressive immunodeficiency in HIV-1 infection

Blood

Antiviral CD8+ T cell responses in neonatal mice: susceptibility to polyoma virus-induced tumors is associated with lack of cytotoxic function by viral antigen-specific T cells

J. Exp. Med.

Viral immune evasion due to persistence of activated T cells without effector function

J. Exp. Med.

Functional diversity of the CD8+ T-cell response to Epstein-Barr virus (EBV): implications for the pathogenesis of EBV-associated lymphoproliferative disorders

Blood

Molecular regulation of interleukin-2 expression by CD28 co-stimulation and anergy

Immunol. Rev.

Functionally heterogeneous CD8+ T-cell memory is induced by Sendai virus infection of mice

J. Virol.

Heterogeneity of the memory CD4 T cell response: persisting effectors and resting memory T cells

J. Immunol.

Uncoupling of proliferative potential and gain of effector function by CD8+ T cells responding to self-antigens

J. Exp. Med.

Heterogeneity of CD4⁺ and CD8⁺ T cells

Acquisition of lymphokine-producing phenotype by CD4⁺ T cells

Activated and memory CD8⁺ T cells can be distinguished by their cytokine profiles and phenotypic markers

Functional heterogeneity of cytokines and cytolytic effector molecules in human CD8⁺ T lymphocytes

Single-cell analysis by RT-PCR reveals differential expression of multiple type 1 and 2 cytokine genes among cells within polarized CD4⁺ T cell populations

Characterization of CD4⁺ CTLs ex vivo

HIV-specific CD8⁺ T cells produce antiviral cytokines but are impaired in cytolytic function

Antiviral CD8⁺ T cell responses in neonatal mice: susceptibility to polyoma virus-induced tumors is associated with lack of cytotoxic function by viral antigen-specific T cells

Functional diversity of the CD8⁺ T-cell response to Epstein-Barr virus (EBV): implications for the pathogenesis of EBV-associated lymphoproliferative disorders

Functionally heterogeneous CD8⁺ T-cell memory is induced by Sendai virus infection of mice

Uncoupling of proliferative potential and gain of effector function by CD8⁺ T cells responding to self-antigens

Phenotypic and functional analysis of CD8⁺ T cells undergoing peripheral deletion in response to cross-presentation of self-antigen