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Th Cell Subsets Th Cell Subsets Dale T. Umetsu, MD, PhD Dale T. Umetsu, MD, PhD February 27, 2002 February 27, 2002 The definition of the Th1/Th2 subsets. The definition of the Th1/Th2 subsets. Situations in which Th subsets Situations in which Th subsets important. important. How do subsets arise and differentiate? How do subsets arise and differentiate? Future directions with this paradigm. Future directions with this paradigm. – Related T cell subsets Related T cell subsets – Regulatory T cell subsets. Regulatory T cell subsets.

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Page 1: Th Cell Subsets Dale T. Umetsu, MD, PhD February 27, 2002 n The definition of the Th1/Th2 subsets. n Situations in which Th subsets important. n How do

Th Cell SubsetsTh Cell SubsetsDale T. Umetsu, MD, PhDDale T. Umetsu, MD, PhD

February 27, 2002February 27, 2002

The definition of the Th1/Th2 subsets.The definition of the Th1/Th2 subsets. Situations in which Th subsets important. Situations in which Th subsets important. How do subsets arise and differentiate? How do subsets arise and differentiate? Future directions with this paradigm.Future directions with this paradigm.

– Related T cell subsetsRelated T cell subsets

– Regulatory T cell subsets. Regulatory T cell subsets.

Page 2: Th Cell Subsets Dale T. Umetsu, MD, PhD February 27, 2002 n The definition of the Th1/Th2 subsets. n Situations in which Th subsets important. n How do

Expression of cytokines by CD4 T cell subsetsExpression of cytokines by CD4 T cell subsets

IL-3IL-3 ++ ++ ++ --

GM-CSFGM-CSF ++ ++ ++

TNF-TNF- ++ ++

Cytokine Th1 Th2 Th0 Thp

IFN-IFN- ++ -- ++--

IL-4IL-4 -- ++ ++--

LymphotoxinLymphotoxin ++ ----

IL-2IL-2 ++ -- ++++

IL-5IL-5 -- ++ ++--

IL-9IL-9 -- ++IL-10IL-10 -- ++

--IL-13IL-13 -- ++

Page 3: Th Cell Subsets Dale T. Umetsu, MD, PhD February 27, 2002 n The definition of the Th1/Th2 subsets. n Situations in which Th subsets important. n How do

Generation of Th Cell linesGeneration of Th Cell lines

DO11.10OVA-specific TCR Tg

Isolate clonotypicCD4+ T cells

OVA + APCrIL-12Anti-IL-4 mAb

OVA + APCrIL-4Anti-IL-12 mAb

OVA + APCrIL-4rIFN-

Th1

Th2

Th0

Page 4: Th Cell Subsets Dale T. Umetsu, MD, PhD February 27, 2002 n The definition of the Th1/Th2 subsets. n Situations in which Th subsets important. n How do

Markers of Th1 and Th2 Markers of Th1 and Th2 CellsCells

Th1 Th2

IFN-IFN-, IL-2, IL-2IL-12RIL-12R22IL-18RIL-18RP- and E- selectin receptorP- and E- selectin receptorCXCR3, CCR5CXCR3, CCR5Tim3Tim3

Stat4, T-betStat4, T-bet

IL-4IL-4IL-1R, IFN-IL-1R, IFN- receptor receptorT1/ST2 (homolog of IL-1R)T1/ST2 (homolog of IL-1R)

CCR3, CCR4, CCR8CCR3, CCR4, CCR8Tim1? ICOSTim1? ICOS

GATA-3, Stat6GATA-3, Stat6

Page 5: Th Cell Subsets Dale T. Umetsu, MD, PhD February 27, 2002 n The definition of the Th1/Th2 subsets. n Situations in which Th subsets important. n How do

Infection with Infection with LeishmaniaLeishmania

C3H/HeN resistantC3H/HeN resistant IFN- IFN-, IL-2, IL-2

BALB/cBALB/c susceptible susceptible IL-4, IL-5, IL-13 IL-4, IL-5, IL-13

StrainStrain result result cytokines produced cytokines produced

Page 6: Th Cell Subsets Dale T. Umetsu, MD, PhD February 27, 2002 n The definition of the Th1/Th2 subsets. n Situations in which Th subsets important. n How do

Disease States Attributed to an Disease States Attributed to an Imbalance in Th1/Th2 Cells Imbalance in Th1/Th2 Cells

Autoimmune diseasesAutoimmune diseasesMultiple sclerosisMultiple sclerosisRheumatoid arthritisRheumatoid arthritisDiabetes mellitusDiabetes mellitusCrohn’s diseaseCrohn’s disease

Graft rejectionGraft rejectionHelminth infectionHelminth infectionAborted pregnancyAborted pregnancy

InfectionsInfectionsLeishmaniaLeishmaniaTB, leprosyTB, leprosyFungal infectionFungal infectionHIVHIV

AllergyAllergyUlcerative colitisUlcerative colitis

Over production Over production Over production Over production of Th2 cytokines of Th2 cytokines of Th1 cytokinesof Th1 cytokines

Page 7: Th Cell Subsets Dale T. Umetsu, MD, PhD February 27, 2002 n The definition of the Th1/Th2 subsets. n Situations in which Th subsets important. n How do

T Cell Subsets: when are they important?T Cell Subsets: when are they important?

During chronic antigen stimulationDuring chronic antigen stimulation– Chronic infectionChronic infection

– Chronic response to auto antigens.Chronic response to auto antigens.

– Chronic exposure to allergens.Chronic exposure to allergens. Not following a single antigenic Not following a single antigenic

stimulation, not with fulminant stimulation, not with fulminant infections. infections.

Page 8: Th Cell Subsets Dale T. Umetsu, MD, PhD February 27, 2002 n The definition of the Th1/Th2 subsets. n Situations in which Th subsets important. n How do

Th1 Cells Cross Regulate Th2 CellsTh1 Cells Cross Regulate Th2 Cells

Th1 cytokinesTh1 cytokines IL-2IL-2 IFN-IFN- IL-12IL-12 Th2 cytokinesTh2 cytokines

IL-4IL-4 IL-5IL-5 IL-13IL-13

IL-12IL-12IFN-IFN-

IL-4IL-4IL-10IL-10

Page 9: Th Cell Subsets Dale T. Umetsu, MD, PhD February 27, 2002 n The definition of the Th1/Th2 subsets. n Situations in which Th subsets important. n How do

What are the instructive signals for What are the instructive signals for the development of Th1/Th2 cellsthe development of Th1/Th2 cells

Cytokine microenvironmentCytokine microenvironment Antigen dose/TCR signalingAntigen dose/TCR signaling

– Altered peptide ligandsAltered peptide ligands APC typeAPC type

– Route of antigen administrationRoute of antigen administration Costimulatory signalsCostimulatory signals Host genetic factorsHost genetic factors

Page 10: Th Cell Subsets Dale T. Umetsu, MD, PhD February 27, 2002 n The definition of the Th1/Th2 subsets. n Situations in which Th subsets important. n How do

Signals that influence Th differentiationSignals that influence Th differentiation

IL-12, TGF-

IL-4, IL-10, TGF-

Page 11: Th Cell Subsets Dale T. Umetsu, MD, PhD February 27, 2002 n The definition of the Th1/Th2 subsets. n Situations in which Th subsets important. n How do

Antigen EffectsAntigen Effects

High antigen dose induces Th1 cell High antigen dose induces Th1 cell differentiation; low dose induces Th2 cell differentiation; low dose induces Th2 cell differentiation.differentiation.

Peptides with high affinity for the TCR Peptides with high affinity for the TCR induces Th1 responsesinduces Th1 responses

Altered peptide ligands induce Th2 Altered peptide ligands induce Th2 responses. responses.

Peptide affinity for TCR alters Peptide affinity for TCR alters phosphorylation of TCR associated proteins. phosphorylation of TCR associated proteins.

Page 12: Th Cell Subsets Dale T. Umetsu, MD, PhD February 27, 2002 n The definition of the Th1/Th2 subsets. n Situations in which Th subsets important. n How do

Transcription factors that influence Transcription factors that influence Th differentiationTh differentiation

T-betT-bet

c-mafc-mafGATA-3GATA-3

Innate immunity

IL-12

Page 13: Th Cell Subsets Dale T. Umetsu, MD, PhD February 27, 2002 n The definition of the Th1/Th2 subsets. n Situations in which Th subsets important. n How do

Agarwal, Rao. 1998. Immunity. 9:765

Page 14: Th Cell Subsets Dale T. Umetsu, MD, PhD February 27, 2002 n The definition of the Th1/Th2 subsets. n Situations in which Th subsets important. n How do

Lafaille, et al. J. Exp. Lafaille, et al. J. Exp. Med 186:307, 1997.Med 186:307, 1997.

Th1(5x106)Th2 (5x106)

Th1(0.2x106)

Th2(0.2x106)

Page 15: Th Cell Subsets Dale T. Umetsu, MD, PhD February 27, 2002 n The definition of the Th1/Th2 subsets. n Situations in which Th subsets important. n How do

Attempts to tolerize with MOG results in exacerbation. Genain, et al. 1996. Science. 274:2054

Page 16: Th Cell Subsets Dale T. Umetsu, MD, PhD February 27, 2002 n The definition of the Th1/Th2 subsets. n Situations in which Th subsets important. n How do

Transfer of diabetes with both Th1 and Th2 cellsPakala, et al. 1997. JEM. 186:299.

Page 17: Th Cell Subsets Dale T. Umetsu, MD, PhD February 27, 2002 n The definition of the Th1/Th2 subsets. n Situations in which Th subsets important. n How do

Th1 cells do not inhibit Th2 cell-induced Th1 cells do not inhibit Th2 cell-induced airway hyperreactivityairway hyperreactivity

0

200

400

600

800

% a

bove b

aselin

e

0 10 20 30 40 50

Methacholine (mg/ml)

none

Th1

Th1+Th2 (2:1)

Th1+Th2 (1:1)

Th2

transferred cells:

Hansen, et al J.C.I. 1997

Page 18: Th Cell Subsets Dale T. Umetsu, MD, PhD February 27, 2002 n The definition of the Th1/Th2 subsets. n Situations in which Th subsets important. n How do

The Th1/Th2 Paradigm and The Th1/Th2 Paradigm and Disease RegulationDisease Regulation

Both Th1 and Th2 cells cause disease.Both Th1 and Th2 cells cause disease. The “opposite” of Th1 cells is not a Th2 The “opposite” of Th1 cells is not a Th2

cell.cell. The Th1/Th2 paradigm cannot fully explain The Th1/Th2 paradigm cannot fully explain

immune regulation.immune regulation. Additional regulatory cells must exist to Additional regulatory cells must exist to

regulate immune responses. regulate immune responses.

Page 19: Th Cell Subsets Dale T. Umetsu, MD, PhD February 27, 2002 n The definition of the Th1/Th2 subsets. n Situations in which Th subsets important. n How do

Tr1 CellsTr1 Cells

Develop after stimulation with IL-10.Develop after stimulation with IL-10. Produce IL-10, IL-5, (TGF-Produce IL-10, IL-5, (TGF-. . Inhibitory for experimental colitis. Inhibitory for experimental colitis. Anti-IL-10 mAb reverses inhibitory effect. Anti-IL-10 mAb reverses inhibitory effect. Low proliferative capacity.Low proliferative capacity. Mature DCs producing IL-10 induce Tr1 Mature DCs producing IL-10 induce Tr1

cells. cells.

Page 20: Th Cell Subsets Dale T. Umetsu, MD, PhD February 27, 2002 n The definition of the Th1/Th2 subsets. n Situations in which Th subsets important. n How do

Th3 CellsTh3 Cells

Generated by oral tolerance induction with Generated by oral tolerance induction with low dose antigen.low dose antigen.

Produce TGF-Produce TGF-, IL-4, IL-4 Express regulatory/suppressive activity. Express regulatory/suppressive activity. TGF-TGF- production may be enhanced by production may be enhanced by

cross-linking of CTLA-4. cross-linking of CTLA-4.

Page 21: Th Cell Subsets Dale T. Umetsu, MD, PhD February 27, 2002 n The definition of the Th1/Th2 subsets. n Situations in which Th subsets important. n How do

CD45RBCD45RBlowlow Cells, CD25 Cells, CD25++ Cells Cells

CD25CD25++. . When transferred, have strong When transferred, have strong

regulatory/suppressive activity for colitis regulatory/suppressive activity for colitis and diabetes. and diabetes.

Appear to require TGF-Appear to require TGF- and IL-10 to and IL-10 to function. function.

CTLA-4 signaling required.CTLA-4 signaling required. Antigen specificity?Antigen specificity?

Page 22: Th Cell Subsets Dale T. Umetsu, MD, PhD February 27, 2002 n The definition of the Th1/Th2 subsets. n Situations in which Th subsets important. n How do

high antigen

uncommitted CD4+ T cell

Th1 Th2 Th3 Tr1

Th?

CD8 T cell

20002000

CD45RBlow

Page 23: Th Cell Subsets Dale T. Umetsu, MD, PhD February 27, 2002 n The definition of the Th1/Th2 subsets. n Situations in which Th subsets important. n How do

Summary-T cell subsetsSummary-T cell subsets

A major theme in immunology, and A major theme in immunology, and documented feature of the immune system.documented feature of the immune system.

Subsets of T cells express restricted Subsets of T cells express restricted cytokine profilescytokine profiles

Cells with restricted cytokine profiles (CD4, Cells with restricted cytokine profiles (CD4, CD8, NK, NK T, B) have distinct effector CD8, NK, NK T, B) have distinct effector functions and regulate immune responses. functions and regulate immune responses.

Page 24: Th Cell Subsets Dale T. Umetsu, MD, PhD February 27, 2002 n The definition of the Th1/Th2 subsets. n Situations in which Th subsets important. n How do

Questions that remainQuestions that remain

What regulatory cells “balance” Th1 and What regulatory cells “balance” Th1 and Th2 cells? What downregulates polarized Th2 cells? What downregulates polarized responses?responses?

How Th subsets are involved in tolerance?How Th subsets are involved in tolerance? What additional molecular mechanisms What additional molecular mechanisms

regulate cytokine synthesis? regulate cytokine synthesis? What are the host/genetic factors that What are the host/genetic factors that

regulate cytokine production?regulate cytokine production?


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