CD4 T-cell diversity

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John O'Shea, Arian Laurence and Adewole Adamson
CD4+ T helper (TH) cells are central players in orchestrating innate and adaptive immune responses. TH cells have been classically considered to belong to one of two subsets TH1 cells or TH2 cells each of which has unique cytokine products, signalling pathways and lineage-specific transcription factors or master regulators. Recently, TH cells that secrete IL-17 (TH17 cells) have emerged as a third lineage of CD4+ TH cells. Together with regulatory T (TReg) cells, which preserve peripheral tolerance, these two newly described Tcell subsets have raised fundamental questions about lineage commitment and fate determination of CD4+ T cells. This Poster depicts the various cytokines, transcription factors and signalling pathways that are associated with the differentiation, survival and function of CD4+ effector T cells. The differentiation of CD4+ Tcells is typically depicted as a one-way route, implying that there is terminal differentiation with little plasticity in cytokine responses. However, recent data argue for more complexity and flexibility than was previously assumed. As with any model, this is a work in progress and subject to enhancement in the coming years.

IMMUNOLOGY

IL-4 IFN, TGF STAT6 GATA3 GATA3 IFN STAT4 IL-12 IL-21 IL-1 IL-2 STAT5 SMAD FOXP3 IL-23 IL-18 RUNX1 STAT3 TNF SMAD IRF4 AHR RUNX1 TGF SMAD FOXP3 IL-17 SOCS3, STAT1, STAT5, FOXP3 IL-23 RORt ROR STAT3 IL-17 RUNX3 TGF, IL-4, IL-21 IFN, IL-2, IL-4, IL-12, IL-27, RA Notch HLX T-bet STAT1 IL-4 STAT1 T-bet GATA3 IL-12 IFN

Naive CD4+ T cell

Antigen-presenting cell TGF RA IL-6, IL-21 IFN IL-6

IL-4 IL-25

STAT6 Notch

IRF4 MAF

JUNB

IL-4, IL-5, IL-10, IL-13, IL-21, IL-31 Humoral immunity, allergy and other functions

TH2 cell

T-bet STAT4

IFN, TNF, lymphotoxin, IL-10 Cell-mediated immunity and type I hypersensitivity

IFNproducing TH17 cell

TH1 cell

Subset flexibility and plasticity

TH17 cell
IL-6 TGF

RORt IL-4, IFN IL-23 IL-6

Inducible TReg cell

IL-17A, IL-17F, IL-21, IL-22 Inflammation and pathogen defence

TGF, IL-10, IL-35 Self tolerance and immune suppression

IL-10producing TH17 cell

IL-10, IL-17A, IL-17F

IL-22producing TH17 cell

IL-21, IL-22, IL-17A, IL-17F, IL-26, CCL20

At present, lineage commitment is defined by the signature cytokines that differentiated cells secrete IFN, IL-17 (IFN, IL-4 and IL-17 for TH1, TH2 and TH17 cells, respectively). However, additional complexity is becoming evident. For example, although TReg cells are thought to be immunosuppressive, all CD4+ T-cell subsets can produce the immunoregulatory cytokine IL-10, which is crucial for dampening immune responses. Furthermore, TH17 cells can also produce IFN, and so the relationship between TH1 cells and TH17 cells is currently being intensively scrutinized. Similarly, although TH17 cells produce IL-21 and IL-22, it also seems that under some circumstances, T cells can produce IL-21 or IL-22 without producing IL-17 (not shown). Another complication is that models that imply the selective expression of master regulators might not be appropriate. For example, FOXP3 and RORt can be co-expressed and can interact. Functionally, it seems that some TReg cells can be induced to become TH17 cells. So, an important issue in the field is whether each CD4+ T-cell subset should be viewed as a terminally differentiated lineage or whether the subsets retain some flexibility. The extent to which some aspects of T-cell subsets are firmly fixed and others remain plastic is the subject of intense investigation.

TH1 cell
IL-12 IL-12R1 IL-12R2 IFNGR1

IFN IFNGR2

Notch ligand

IL-4 Notch receptor IL-4R c

IL-2 c

TH2 cell
IL-2RB IL-2RA

CD4+ T-cell differentiation

Following contact with antigen-presenting cells (APCs), signals generated by the T-cell receptor (TCR) and co-stimulatory molecules initiate the process by which naive CD4+ T cells begin to differentiate towards one of several fates. In the context of an appropriate signal through the TCR, the cytokine milieu that is generated by APCs is an important factor that influences differentiation. IL-12 activates STAT4 and drives naive CD4+ T cells to become TH1 cells, which produce IFN. Signals from the TCR, as well as from IL-12 and IFN (acting through STAT4 and STAT1, respectively), increase the expression of the transcription factor T-bet, which promotes IFN production and commitment to the TH1-cell lineage. TH1 cells are important for host defence against intracellular bacteria. Naive CD4+ T cells are induced to become TH2 cells through the secretion of IL-4 by innate immune cells, which signals through STAT6. This leads to expression of the transcription factor GATA3, in turn resulting in the production of IL-4, IL-5 and IL-13, which are important for host defence against helminths and contribute to the pathogenesis of asthma and allergy. TReg cells can develop from thymic CD4+ T-cell precursors in the presence of TGF and IL-2. These are termed natural TReg cells (not shown). In the periphery, naive CD4+ T cells can also be converted to become inducible TReg cells by signalling through STAT5 in the presence of TGF, which results in upregulation of the transcription factor FOXP3. TReg cells secrete low levels of IL-2 and IFN, and instead they produce high levels of IL-10, IL-35 and TGF. Retinoic acids, which are abundant in the liver and intestine, increase FOXP3 expression. TReg cells have an important role in peripheral self tolerance and immune suppression. TH17 cells develop from naive CD4+ T cells in response to IL-6, IL-21, TGF and IL-1b. IL-6 and IL-21 activate STAT3, which increases the expression of the transcription factors RORt and ROR, which in turn promote the expression of IL-17A, IL-17F, IL-21 and IL-22. IL-23 seems to stabilize and increase the pathogenicity of TH17 cells. TH17 cells are important for host defence against extracellular bacteria and are involved in mediating autoimmune disease.
Cytoplasm STAT6 STAT4
P P P P P

STAT5

STAT1

Intracellular Notch Notch3 Notch1, Notch2

STAT1

STAT6

Nucleus STAT4
P

MAML RBPJ
P

STAT5

GATA3
P

HLX

NFB

MAML RBPJ T-bet T-bet

GATA3 GATA3, GFI1

MAML RBPJ MAF NFAT2 AP1

IFN, TNF, lymphotoxin

IL-4, IL-5, IL-13

Inducible TReg cell

AHR ligand Retinoic acid c

IL-2

TGF IL-2RB TGFR

IL-6 IL-6ST R-SMAD IL-6R

IL-21 IL-27 c IL-21R IL-6ST IL-27RA IL-1RAP

TH17 cell
IL-1 IL-1R1

IL-2RA

STAT5

STAT3

Cytoplasm AHR HSP90

R-SMAD Co-SMAD ?

SOCS3 STAT1 RAR

P P

STAT5

FOXP3

R-SMAD Co-SMAD FOXP3

STAT3

RUNX1

STAT3?

Nucleus

RAR

AHR ? ARNT ?
P

RUNX1

RUNX1 RORt ROR

TGF, IL-10, IL-35

ETS1

RORt, ROR

IL-17A, IL-17F, IL-21, IL-22

c, common cytokine receptor -chain; AHR, aryl hydrocarbon receptor; AP1, activator protein 1; ARNT, aryl receptor nuclear transporter; CCL20, CC-chemokine ligand 20; Co-SMAD, co-mediator SMAD; FOXP3, forkhead box P3; GATA3, GATA-binding protein 3; GFI1, growth-factor independent 1; HLX, H2.0-like homeobox 1; HSP90, heat-shock protein 90; IFN, interferon-; IL, interleukin; IL-1RAP, IL-1 receptor accessory protein; IL-6ST, IL-6 signal transducer; IRF, interferon-regulatory factor; MAML, Mastermind-like; NFAT, nuclear factor of activated Tcells; NF-B, nuclear factor-B; RA, retinoic acid; RAR, retinoic acid receptor; RBPJ, recombination-signal-binding protein for immunoglobulin- J region (also known as CSL); ROR, retinoic-acid-receptor-related orphan receptor; R-SMAD, receptor-regulated SMAD; RUNX, Runt-related transcription factor; SMAD, mothers against decapentaplegic homologue; SOCS3, suppressor of cytokine signalling 3; STAT, signal transducer and activator of transcription; TGF, transforming growth factor-; TNF, tumour-necrosis factor.

Abbreviations

Affiliations
John OShea, Arian Laurence and Adewole Adamson are at the Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA. e-mail: osheaj@arb.niams.nih.gov Edited by Lucy Bird and Kirsty Minton; copy edited by Rachel David; designed by Simon Bradbrook.

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