04 Effector T Cells Cytokines
Transcript of 04 Effector T Cells Cytokines
-
8/3/2019 04 Effector T Cells Cytokines
1/14
1
Effector T Cells andCytokines
Andrew Lichtman, MD PhDBrigham and Women's Hospital
Harvard Medical School
2
Lecture outline
Cytokines
Subsets of CD4+ T cells: definitions,functions, development
New therapeutic strategies targetingcytokines
-
8/3/2019 04 Effector T Cells Cytokines
2/14
3
Cytokines
Secreted proteins that mediate andregulate immunity and inflammation About 180 cytokines in the genome, about
30 well defined so far (excluding chemokines)
Produced by many cell types (mostly cellsof the immune system), act on diversetargets (often white blood cells)
The interleukin nomenclature
Most act near site of production; bloodcytokine assays are usually notinformative (except in severe infections?)
Take home messages
4
Therapeutic Targeting of Cytokines
TNF antagonists (RA, IBD, Psoriasis)
IL-1RA (RA) IL-2R (Kidney transplant rejection)
IL-6 antagonists (RA, Multiple Myeloma)
Anti- IL- 1 2p40 (IBD, RA)will inhibit TH1 and TH1 7
Anti-IL-17 (Psoriasis, RA)
Anti-IL-4 (Asthma) Anti-IL-5 (Asthma) Anti- type I IFN (SLE)
-
8/3/2019 04 Effector T Cells Cytokines
3/14
5
The life history of T lymphocytes
Precursors mature in the thymus
Nave CD4+ and CD8+ T cells enter the circulation
Nave T cells circulate through lymph nodesand find antigens
T cells are activated and develop into
effector and memory cells
Effector T cells migrate to sites of infection
Eradication of infection
6
Functions of CD4+ T cells are mediated by cytokines
-
8/3/2019 04 Effector T Cells Cytokines
4/14
7
Induction of T cell responses
Cytokines produced byAPCs and other cells at
time of antigen recognition
8
Effector phase of T cell responses
Cytokines produced byeffector T cells at time of
microbe (antigen)elimination
-
8/3/2019 04 Effector T Cells Cytokines
5/14
9
Discovery of Th1 and Th2 subsets
Immune responses to mycobacteria andhelminths are very different but CD4+ Tcells are required for both How can the same CD4+ T cells trigger such
distinct reactions?
Hypothesis: CD4+ T cells consist ofsubpopulations that mediate different
responses
Identification of mouse CD4+ T cellclones that produce distinct cytokines
10
Discovery of the Th17 subset
Inflammatory diseases (e. g. mouse modelof multiple sclerosis) previouslyattributed to Th1 reactions wereworsened by eliminating IFN, thesignature cytokine of Th1 cells
Disease shown to be dependent on acytokine IL- 23 (related to IL- 1 2)
IL- 23 stimulates the development ofCD4+ T cells that produce IL- 17
-
8/3/2019 04 Effector T Cells Cytokines
6/14
11CD4+ TH subsets
Nave
CD4+ T cell
TH1
TH2
TH1 7
IFN
IL-4IL-5
IL-13
IL-17IL-21IL-22
APC
Cytokinesproduced
Hostdefense
Role indiseases
Immunereactions
Macrophageactivation;
IgG
production
Mast cell,
eosinophilactivation;
IgE production;alternative
macrophage
activation
Neutrophilic,monocyticinflammation
Intracellularmicrobes
Helminthic
parasites
Extracellularbacteria;fungi
Autoimmunediseases;
tissue damage
associated withchronic infections
Atopic
diseases
Organ-specificautoimmunity
Take home messages
12
CD4+ T cell subsets: definitions andgeneral properties
Populations of CD4+ T cells that makerestricted and non- overlapping sets ofcytokines
Early after activation, T cells can producemultiple cytokines
Progressive activation leads to polarization:production of selected cytokines
Distinct functions, migration properties,roles in disease
-
8/3/2019 04 Effector T Cells Cytokines
7/14
13
Effector functions of TH1 Cells
Effector functions of TH2 Cells
Antibodyproduction
Antibody
production
IgG4 (human),IgG1 (mouse)
-
8/3/2019 04 Effector T Cells Cytokines
8/14
15
Some common misconceptions about Th1
and Th2 subsets
MISCONCEPTION: Th1 = cell- mediatedimmunity, Th2 = humoral immunity
FACT: the production of the most useful IgGantibodies is dependent on IFN; Th2 cellsstimulate the production of very few Igisotypes (IgE, IgG4)
MISCONCEPTION: Th1 and Th2 subsets exist
only in mice and are not found in humans FACT: prolonged immune stimulation induces
Th1 and Th2 cells even in humans(autoimmune diseases, allergies)
16
Effector functions of TH17 Cells
InflammationInflammation
Chemokine
s, TNF, IL-1,CSF
s
-
8/3/2019 04 Effector T Cells Cytokines
9/14
17
Differentiation of Th subsets fromnave CD4+ T cells: general principles
Different subsets develop from thesame nave CD4+ T cells
Cytokines produced at the site ofantigen recognition drive differentiationinto one or the other subset
Major sources of cytokines: APCs,responding T cells themselves , other
host cells Each subset is induced by the types of
microbes that subset is best able tocombat
Take home messages
18
Differentiation of Th subsets from nave Tcells: general principles - - 2
Process of Th differentiation consist of 3phases:
1 . Induction: production of subset- specifictranscription factors, synthesis of
subset- specific cytokines2. Commitment: epigenetic changes in
cytokine gene loci lead to stable cytokineproduction
3. Amplification: cytokines produced by Tcells promote development of more of thesame subset and suppress development ofother subsets
Take home messages
-
8/3/2019 04 Effector T Cells Cytokines
10/14
19
Development ofTh subsetsfrom nave
CD4+ T cells
20
TH differentiation:Cytokines determinelineage commitment
NaveCD4+ T cell
TH1
TH2
TH1 7
TGF-IL-6 or IL-1
IL-23
IFNIL-12
IL-4
IFN
IL-4IL-5IL-13
IL-17IL-21IL-22
DC APC
?
-
8/3/2019 04 Effector T Cells Cytokines
11/14
21
TH differentiation:
Transcription factors
Nave CD4+
T cell
TH1
TH2
TH1 7
TGF-IL-6 or IL-1IL-23
IFNIL-12
IL-4
T-bet(Stat 1, Stat 4)
GATA3(Stat 6)
RORT(Stat 3)
IFN
IL-4IL-5IL-13
IL-17IL-21IL-22
DC APC
22Th subset differentiation
Th1 Th2 Th17
-
8/3/2019 04 Effector T Cells Cytokines
12/14
23
Th1 cells (IFN- )
Th17 cells (IL- 1 7)Nave CD4
T cell
Regulatory T cells
IFN
- ,IL-
12
T-bet
,Sta
t4
TGF- + IL-6ROR-t;Stat3T
GF-IL-2
FoxP3, Stat5
Th2 cells (IL- 4)IL-4
GATA-3
, Stat6
Regulatory T cells are another subset
24
Follicular helper T cells (Tfh)
Characteristics of Tfh: Express CXCR5, ICOS Transcription factor: BCL- 6 Cytokines secreted: IL-21 + IL- 4 or IFN (or IL- 1 7?)
Functions of: Migrate to lymphoid follicles, and help B cells (class
switching, affinity maturation)
Th1
Th17
Nave CD4T cell
Th2
Follicular helperT cells (Tfh)
IL-21
BCL-6
Treg
-
8/3/2019 04 Effector T Cells Cytokines
13/14
25
Helper T cell subsets: progress and
questions Elucidation of CD4+ subsets has revealed
fundamental aspects of control and functions ofimmune responses
Cytokines that drive subset development (e. g.IL- 1 2/IL-23 p40) or are produced by differentsubsets (e.g. IL- 17A) are important therapeutictargets
Unresolved questions:
Signals that induce different subsets in vivo How stable or plastic are these subsets?
Cross- regulation of subsets: when aredifferent populations induced and how do theyaffect one another?
Take home messages
26
Roles of T cell subsets in disease
Th1: autoimmune and inflammatorydiseases (IBD?, MS?, RA?; tissue damagein infections (e. g. Tb) Activation of macrophages, CTL responses;
production of injurious antibodies
Th2: allergies (e. g. asthma) Stimulation of IgE responses, activation of
eosinophils
Th17: inflammatory diseases (MS, IBD,RA) Recruitment of leukocytes
-
8/3/2019 04 Effector T Cells Cytokines
14/14
27
TCR
CD28
IL- 12, IL- 23(p40)
T cellT cell
IL-2
Calcineurin, mTORinhibitors
(inhibit signaling)
Anti- IL- 2R(block cytokine
receptor)
CTLA-4.Ig(block costimulation)
TNF, IL- 1 IL- 17A
APC
Anti- p40TNF, IL- 1antagonists
(block cytokines)
Anti- IL- 17A
InflammationAnti- integrin
antibodies(block adhesion)
Development of rational therapy: a triumph of Immunology