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


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)


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


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


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


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


7/14

13

Effector functions of TH1 Cells


Antibodyproduction

Antibody

production

IgG4 (human),IgG1 (mouse)


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


InflammationInflammation

Chemokine

s, TNF, IL-1,CSF

s


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


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

?


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


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


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


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

Documents

04 Effector T Cells Cytokines