Th Cell Subsets Dale T. Umetsu, MD, PhD February 27, 2002 n The definition of the Th1/Th2 subsets. n...
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Transcript of Th Cell Subsets Dale T. Umetsu, MD, PhD February 27, 2002 n The definition of the Th1/Th2 subsets. n...
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.
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 -- ++
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
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
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
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
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.
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
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
Signals that influence Th differentiationSignals that influence Th differentiation
IL-12, TGF-
IL-4, IL-10, TGF-
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.
Transcription factors that influence Transcription factors that influence Th differentiationTh differentiation
T-betT-bet
c-mafc-mafGATA-3GATA-3
Innate immunity
IL-12
Agarwal, Rao. 1998. Immunity. 9:765
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)
Attempts to tolerize with MOG results in exacerbation. Genain, et al. 1996. Science. 274:2054
Transfer of diabetes with both Th1 and Th2 cellsPakala, et al. 1997. JEM. 186:299.
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
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.
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.
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.
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?
high antigen
uncommitted CD4+ T cell
Th1 Th2 Th3 Tr1
Th?
CD8 T cell
20002000
CD45RBlow
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.
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?