T cells: the usual subsets
Chen Dong and Gustavo J. Martinez
T cells have important roles in immune responses and function by directly secreting soluble mediators orthrough cell contact-dependent mechanisms. Many T cell subsets have been characterized. Although
effector T cells were originally considered to be terminally differentiated, a growing body of evidence has
challenged this view and suggested that the phenotype of effector T cells is not completely fixed but ismore flexible or plastic. T cells can have ‘mixed’ phenotypes (that is, have characteristics usuallyassociated with more than one T cell subset) and can interconvert from one subset phenotype to another,although instructive signalling can lead to long-term fixation of cytokine memory. T cell plasticity can be

IMMUNOLOGY

important for adaptation of immune responses in different microenvironments and might be particularly
relevant for host defence against pathogens that colonize different tissues. Distinct T cell subsets, ordifferentiation states, can be identified based on the cell surface markers expressed and/or the effector
molecules produced by a particular T cell population. This Poster summarizes our current understanding of
the surface markers, transcriptional regulators, effector molecules and functions of the different T cellsubsets that participate in immune responses. Further knowledge of how these T cell subsets are regulated
and cooperate with each other will provide us with better tools to treat immune-related diseases.

Cytotoxic T cell

Exhausted T cell

Anergic T cell

TR1 cellNatural TReg cellSurfacephenotypeTranscription
factors
Effector
molecules
secretedFunction

SurfacephenotypeTranscription
factorsFunction

Surfacephenotype
Effectorfactors
Function

Surfaceαβ TCR, CD3, CD4
phenotypeTranscription Not known
factors

Surface phenotype
Transcription factors
Effector molecules secreted
Function

Otherfeatures

αβ TCR, CD3, CD8
EOMES, T-bet, BLIMP1
Perforin, granzyme, IFNγ

Cytotoxic; kill infected andtransformed cells and thereby
protect the host from viral
infections and cancer. Direct
killing is mediated by secretion ofperforin and granzymes, whichcause apoptosis of target cells.
In humans, mainly CD45RO+. Someterminally differentiated CTLs inhumans re-express CD45RA.

CD3, CD8, PD1,TIM3, 1B11, LAG3
BLIMP1
Generated in responseto chronic antigenmediated TCR
stimulation. Thesecells express inhibitory
receptors and lackeffector cytokine
production; they
therefore fail to mounteffective antiviral
immune responses.

Otherfeatures

10’0µm

TCR

TCR
IL-7R

Other features

NaiveLAG3

Exhausted

Cytotoxic

IL-10

Function

Immunosuppression
mediated by IL-10
production. These cells
are generated from naive
T cells in the presence ofTGFβ and IL-27 or in thepresence of the immuno­
suppressive drugs
vitamin D3 anddexamethasone.

BTLA

Cytokine
receptor

Inducible TReg cellSurface phenotype
Transcription factors
Effector molecules secretedFunction

CD4
Chemokine
receptor

CD3

TCR
GITR

CD3

αβ TCR, CD3, CD4, CD25, CTLA4, GITR
FOXP3, FOXO1, FOXO3, STAT5, SMAD2, SMAD3, SMAD4
IL-10, TGFβ
Promote immunosuppression and tolerance bycontact-dependent and -independent mechanisms.
These cells are generated from naive T cells in theperiphery and, at least in some cases, TGFβ and IL-2
are important for their differentiation.

Surface phenotype NK1.1, SLAMF1, SLAMF6, TGFβR,Vα14, Jα18 (mouse)
Vα24, Jα18 (human)
Transcription
PLZF
factors
Effector molecules IL-4, IFNγ, IL-17A
secreted
Function
Can have both pro- and anti-inflammatory
functions. Have been shown to modulate immune
responses in several different settings, including
cancer, autoimmunity, allergy, infection and graftversus-host disease.
Other features
SAP expression. CD1-restricted TCR.
MAIT cells express an invariant TCR α-chain(Vα33Jα19 in mice; Vα7.2Jα19 in humans).
MAIT cells are MR1 restricted (not CD1 restricted)
but have similarities to NKT cells.

Surfacephenotype
Effector
molecules
secretedFunction

CD4
SLAMF1

CTLA4

CD3HelperAnergic

CD25TCR
CD44

CD3TCR

NK1.1IL-7R

SLAMF6αβ or γδ TCR, CD3,CD8αα, B220
IL-10, TGFβIntraepithelial lymphocytes
are found in the gut. They candevelop intra- or extrathymically. They express αβ orγδ TCRs. γδ TCR+ cells express
KGF, whereas αβ TCR+ cells donot. Most αβ TCRs areenriched for self-reactivity.
They require β2 microglobulindependent MHC class Iexpression for their generation
and/or homeostasis. They canhave regulatory functions
through the production ofIL-10 and TGFβ.

γδ TCR
TGFβR

TCR

CD3

CD8αα
B220

CD3

αβ TCR, CD3, CD4, CCR7, CD62Lhi, IL-7R (CD127)
THPOKPatrol through lymph nodes scanning peptide–
MHC class II molecule complexes on APCs forthe presence of their cognate antigen. Following
activation by APCs, naive CD4+ T cells
differentiate into effector or regulatory T cells;
activated naive T cells also give rise to memory
T cells.
CD45RA expressed by human cells.

αβ TCR, CD3, CD8, CCR7, CD62Lhi, IL-7R (CD127)
RUNX3Patrol through lymph nodes scanning peptide–
MHC class I molecule complexes for thepresence of their cognate antigen. Following
activation by APCs, they differentiate into
CTLs and memory T cells.
CD45RA expressed by human cells.

Surface phenotype
Transcription factors
Effector molecules secretedFunction

αβ TCR, CD3, CD4, IL-12R, IFNγR, CXCR3
T-bet, STAT4, STAT1
IFNγ, IL-2, LTα
Promote protective immunity against intracellular pathogens. By secreting
IFNγ, they induce activation of macrophages and upregulation of iNOS,
leading to the killing of intracellular pathogens such as Leishmania major,
Listeria monocytogenes and Mycobacterium spp. Their development isregulated by IL-12.

Other features

αβ TCR, CD3, CD4, IL-4R, IL-33R, CCR4, IL-17RB, CRTH2
GATA3, STAT6, DEC2, MAF
IL-4, IL-5, IL-13, IL-10
Promote humoral immune responses and host defence against extracellularparasites. However, they can also potentiate allergic responses and asthma.
Their development and maintenance is regulated by IL-4, IL-25 and IL-33.
IRF4 is also an important transcription factor.

TH9 cell
Surface phenotype
Transcription factors
Effector molecules secreted
Function

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includes customer reviews, frequently asked questions and scientificSurface phenotype
Transcription factors
Effector molecules secreted
Function

Other features

TH2 cell
Surface phenotype
Transcription factors
Effector molecules secreted
Function

Regulatory

MemoryTH17 cell

αβ TCR, CD3, CD4
PU.1IL-9, IL-10
Involved in host defence against extracellular parasites, primarily
nematodes. Despite their production of anti-inflammatory IL-10, they
promote allergic inflammation. Their role in other inflammatory diseases
still remains unclear as this subset has only recently been characterized.

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nri_poster_sep10.indd 1TCR

TH1 cellCD8 αβ T cellOther features

Effector
molecules
secretedCD8αα T cell

CCR7+Surface phenotype
Transcription
factors
Function

TCR

TIM3 1B11CD3CD4+ αβ T cellSurface phenotype
Transcription
factors
Function

These cells are generated
following TCR activation in
the absence of co-stimulatory
signals, which leads them
to become unresponsive tosubsequent stimulatory signals.
They are functionally inactive
cells and fail to proliferate or
produce IL-2. Their generation
may be important for avoiding
autoimmune responses.
Increased expression of p27KIP1,
which leads to cell cycle arrest.

αβ TCR, CD3, CD4, CD25, CTLA4, GITR
FOXP3, STAT5, FOXO1, FOXO3
IL-10, TGFβ, IL-35
Mediate immunosuppression and tolerogenic responses
through contact-dependent and -independent
mechanisms. These cells are generated in the thymus.

CCR7

6’0µm
4’0µm

CD8 PD1

CD62L

CD3

GRAIL, CBL-B, ITCH, NEDD4

CD8

CD3

8’0µm

αβ TCR, CD3, BTLANKT cell

αβ TCR, CD3, CD4, IL-23R, CCR6, IL-1R,
CD161 (human only)
RORγt, STAT3, RORα
IL-17A, IL-17F, IL-21, IL-22, CCL20
Promote protective immunity against extracellular bacteria and fungi,
mainly at mucosal surfaces. Also promote autoimmune and inflammatory
diseases. Generated in the presence of TGFβ and IL-6 and/or IL-21 and aremaintained by IL-23 and IL-1.
Also express BATF, IκBζ, IRF4 and AHR transcription factors. Human TH17 cells
also produce IL-26.

TH22 cellSurface phenotype
Transcription factors
Effector molecules secretedFunction

αβ TCR, CD3, CD4, CCR10
AHR
IL-22
Identified in inflammatory skin diseases. Their role in host defence remains
unclear as this subset has only recently been characterized. Their identity as anindependent TH cell subset needs to be confirmed.

TFH cell
Surface phenotype
Transcription factors
Effector molecules secretedFunction
Other features

αβ TCR, CD3, CD4, CXCR5, SLAM, OX40L, CD40L, ICOS, IL-21R, PD1
BCL-6, STAT3
IL-21
These cells are involved in promotion of germinal centre responses andprovide help for B cell class switching.
SAP expression.

Abbreviations

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AHR, aryl hydrocarbon receptor; APC, antigen-presenting cell; BATF, basic leucine zipper
transcription factor, ATF-like; BCL-6, B cell lymphoma 6; BLIMP1, B lymphocyte-induced maturation
protein 1; BTLA, B and T lymphocyte attenuator; CBL-B, Casitas B-lineage lymphoma B;
CCL, CC-chemokine ligand; CCR, CC-chemokine receptor; CRTH2, chemoattractant receptorhomologous molecule expressed on TH2 cells; CTL, cytotoxic T lymphocyte; CTLA4, cytotoxicT lymphocyte antigen 4; CXCR, CXC-chemokine receptor; EOMES, eomesodermin; FOX,forkhead box; GATA3, GATA-binding protein 3; GITR, glucocorticoid-induced TNF-receptorrelated protein; GRAIL, gene related to anergy in lymphocytes; IκBζ, inhibitor of NF-κB-ζ; ICOS,inducible T cell co-stimulator; IFNγ, interferon-γ; IL, interleukin; iNOS, inducible nitric oxide
synthase; IRF4, interferon-regulatory factor 4; ITCH, itchy homologue E3 ubiquitin protein ligase;CD8ααγδNKTCentral memory T cellγδ T cellSurface phenotype

Surfacephenotype
Effector
molecules
secreted
FunctionTranscription factors
Effector molecules
secretedFunction

CCR7hi, CD44, CD62Lhi, TCR, CD3,
IL-7R (CD127), IL-15R
BCL-6, BCL-6B, MBD2, BMI1
IL-2, CD40L
Low levels IL-4, IFNγ, IL-17A
Preferentially reside in secondary lymphoidorgans, mounting recall responses toantigens. Even though these cells lack
immediate effector functions, they rapidly
proliferate and differentiate into effector
T cells following antigen stimulation.

Effector memory T cellSurface phenotype
Transcription factors
Effector molecules
secretedFunction

CD62Llow, CD44, TCR, CD3, IL-7R (CD127),
IL-15R, CCR7low
BLIMP1
Rapid and high production of inflammatory
cytokines
Preferentially found in peripheral tissues.
They provide immediate protection uponantigen challenge through, for example, therapid production of effector cytokines.

J, joining region; KGF, keratinocyte growth factor; L, ligand; LAG3, lymphocyte activation gene 3;
LTα, lymphotoxin-α; MAF, musculoaponeurotic fibrosarcoma oncogene; MAIT, mucosal-associatedinvariant T; MBD2, methyl-CpG-binding domain protein 2; MR1, MHC-related protein 1; NEDD4,neuronal precursor cell-expressed developmentally downregulated 4; NKT, natural killer T;
p27KIP1, p27 kinase inhibitory protein 1; PD1, programmed cell death 1; PLZF, promyelocytic
leukaemia zinc-finger; R, receptor; ROR, retinoic acid receptor-related orphan receptor; RUNX3,Runt-related transcription factor 3; SAP, SLAM-associated protein; SLAM, signalling lymphocytic
activation molecule; SMAD, mothers against decapentaplegic homologue; STAT, signal transducer
and activator of transcription; TCR, T cell receptor; TFH, T follicular helper; TGFβ, transforming
growth factor-β; THPOK, TH-inducing POZ/Kruppel-like factor; TH, T helper; TIM3, T cell
immunoglobulin domain and mucin domain protein 3; TLR, Toll-like receptor; V, variable region.

Otherfeaturesγδ TCR, CD3
IFNγ, IL-17A, IL-17F, IL-22

Enriched at epithelial surfaces
and can have both pro- andanti-inflammatory functions,depending on the γδ TCRand the context. Have
characteristics of both innate
and adaptive immunity.
IFNγ- and IL-17A-producing
cells are distinct populations
that can be distinguished by
CD27 and CCR6 expression.
Innate immune recognition byexpression of TLRs.

Affiliations
Chen Dong and Gustavo J. Martinez are at theDepartment of Immunology, M.D. Anderson Cancer
Center and Graduate School of Biomedical Sciences,
University of Texas Health Science Center at Houston,
Houston, Texas 77030, USA.
Edited by Yvonne Bordon; copyedited by Gemma Ryan;
designed by Simon Bradbrook.
© 2010 Nature Publishing Group.
http://www.nature.com/reviews/posters/Tcellsubsets

02/11/2011 15:26