Download T helper cell differentiation and memory

T helper cell differentiation and memory
Birgit Sawitzki
Institute for Medical Immunology
What is the difference between naive and memory T cells?
cytokine memory
•  Effector functions (e.g. cytokine profile)
•  Activation requirements (TCR, co-stimulation)
•  Migratory behaviour (adhesion molecules, chemokine receptors)
•  Response time
•  Life span
Recirculation of lymphocytes
Peripheral tissues
lymph nodes
lymph follicles
lung
naive
regional
Lymph nodes
effector/memory
BALT
GALT
blood
Spleen
gut
bone marrow
thymus
Cytokine memory
memory expression
- speedy
- simultaneous
- signal independent (only TCR)
IL-12/IL-4
antigen
presenting
cell
CD80/86"
CD28"
IL-2 IL-4
INF-γ
IL-10
antigen
presenting
cell
MHCII!
MHCII!
TCR"
TCR"
Th
Th1/2
days
hours
DRFZ
Growing diversity of T helper subsets
cytokine memory
Thnaive
Th1
Th2
Th1
Th2
Th9
TFH
Th17
Treg
Th9
TFH
Th17
Treg
Signature cytokine
IFN-γ, TNF-α,
TNF-β
IL-4, IL-5, IL-10,
IL-13
IL-9
Transcription factor
T-bet, STAT4, Hlx
STAT6, GATA3, cmaf (IRF4)
IRF4
Inducing cytokine
IL-12, IL-18,
IL-27, IFN-γ
IL-4
TGF-β, IL-4
Pathogen-specific
immunity
Intracellular
bacteria, viruses,
protozoa
extracellular
pathogens
Helminthes,
nematodes
helminthes
Immune pathology
IBD, IDDM, RA,
GVHD
atopic asthma,
allergies
IL-21
IL-17, IL-21, IL-22
TGF-b, IL-10
ROR-γt, (IRF4)
Foxp3
IL-21
IL-6/TGF-β IL-21/
TGF-β, IL-23
TGF-b, IL-10,
IL-2, TSLP
B cell
activation,
antibody
production
Similar to Th1,
mucosal infections
extracellular
bacteria, fungi
dampening
immune
responses to
pathogens
EAE, RA, psoriasis
maintain selftolerance
Differentiation of T helper cell subsets
pre-antigen model
pluripotent model
What determines the fate of naive T cells?
1.  Strength of TCR stimulation (signal 1)
•  affinity between TCR and peptide
bound MHCII
•  highest affinity è Th17 (Ag Sawitzki)
•  higher affinity è Th1
•  lower affinity è Th2
2.  Co-stimulation (signal 2)
•  Th2 responses more affected in CD28 /
B7 deficient mice
•  ICOS / OX40 signalling favours Th2
•  Notch receptor signalling
Notch mediated TH cell differentiation
Determination of Th cell differentiation by cytokines
Th1 cell differentiation
NK cells discussed as
first IFN-γ producers
How do Th1 cells help to fight intracellular pathogens?
NO production,
killing of intracellular bacteria (also by ADCC)
MΦ
perforin + granzyme production,
IL-2
IFN-γ
Th1
CD8+
CTL
killing of infected cells
TNF-α
perforin + granzyme production,
NK
killing of infected cells (also by ADCC)
secretion of e.g. IgG1, IgG3 antibodies
Plasma
cell
neutralisation, opsonization (Fc-R = ADCC,
complement-mediated lysis)
Th2 cell differentiation
Which cells provide the
first IL-4?
Which cells are the first IL-4
producers?
- Recent evidence points to
an important role of basophils
in priming TH2 cells
Nakanishi et. al. Eur J Immunol 2010
How do Th2 cells help to fight worm infections?
Th9
Th17 cell differentiation
How do Th17 cells
help to fight
extracellular pathogens?
+ T cell-dependent antibody production
against cell membran / polysaccharid
structures of extracellular bacteria
è
Probably by high surface ICOS
expression and IL-21/IL-17A production
Immunity
Natural and induced Treg
Review
natural Treg
induced Treg
A
B
Figure 1. Differentiation of Thymic and Induced Treg Cells
How Tregs suppress T cell activation and effector function
Th17 vs. iTreg differentiation
Importance of IL-2 for Th and Treg differentation
Boyman et. al. Nature Reviews Immunology 2012
T follicular helper T cells
•  distinct Th cell subset in LN, characterized by CXCR5, ICOS, PD-1 and IL-21 expression
•  migrate to B-cell follicles (germinal centers) via CXCR5-CXCL13 interaction
•  provide B-cell help promoting differentiation and Ig class switch
King et. al. Nature Reviews Immunology 2009
Th cell differentiation in mice and humans
Plasticity and interconvertibility of effector T cells
Plasticity and interconvertibility of effector T cells
Co-expression of different master switch transcription factors
Nakayamada et. al. Current Opinion in Immunology 2012