1 1 Immune Regulation, Tolerance, and Autoimmunity - PowerPoint Presentation

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Immune Regulation, Tolerance, and AutoimmunityMark S. Anderson, MD, PhDUCSFSlide2

Disclosures

Research support from Juno TherapeuticsConsultant for Sanofi2Slide3

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Lecture outlinePrinciples of immune regulation Self-tolerance; mechanisms of central and peripheral

toleranceInhibitory receptors of T cells Treg’s and IL-2Slide4

Activation

Effector T cells

Normal: reactions against pathogens

Inflammatory

disease, e.g. reactions against self

Tolerance

Regulatory T cells

Controlled response to pathogens

No response to self

The immunological equilibrium: balancing

lymphocyte activation and control

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The principal fate of lymphocytes that recognize self antigens in the generative organs is death (deletion), BUT:Some B cells may change

their specificity (called “receptor editing”)Some T cells may differentiate into regulatory (suppressor)

T lymphocytes

Central and peripheral tolerance to self

Abbas,

Lichtman

and

Pillai

.

Cellular and Molecular Immunology, 7

th

edition, 2011

c

ElsevierSlide6

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Consequences of self antigen recognition in thymusAbbas, Lichtman

and Pillai. Cellular and Molecular Immunology, 7th edition, 2011

c

ElsevierSlide7

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What self antigens are seen in the thymus?

Ubiquitous cell-associated and circulating proteins

The thymus has a special mechanism for displaying peripheral tissue antigens in thymic medullary epithelial cells, where they signal self-reactive thymocytes for death Slide8

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Consequences of AIRE mutationHuman disease: autoimmune polyendocrinopathy with candidiasis and

ectodermal dysplasia (APECED), also called autoimmune polyendocrine syndrome (APS-1)Associated gene identified by positional cloning, named AIRE (“autoimmune regulator”)

Mouse knockout:

autoantibodies

against multiple endocrine organs, retina

Failure to express many self antigens in the thymus --> failure of negative selectionSlide9

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Deletion of self-reactive T cells in the thymus:

how are self antigens expressed in the thymus?AIRE (autoimmune regulator) is a regulator of gene transcription

that stimulates thymic

expression of many self

antigens

which

are largely restricted

to peripheral tissues

Abbas,

Lichtman

and

Pillai

.

Cellular and Molecular Immunology, 8

th

edition, 2014 Slide10

NOD.Aire

GW/+ mice develop peripheral neuropathy (CIDP)

Sciatic NerveSlide11

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Peripheral T cell toleranceAbbas, Lichtman and Pillai

. Basic Immunology, 4th edition, 2014 Slide12

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T cell

anergy

Abbas,

Lichtman

and

Pillai

.

Cellular and Molecular Immunology, 7

th

edition, 2011

c

ElsevierSlide13

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APC

APC

T Cell

CD28

B7

Costimulation



T cell activation

B7

CTLA-4

CTLA-4 blocks and removes B7

 lack of

costimulation



T cell inhibition

CTLA-4 competitively inhibits B7-CD28 engagement

T

c

ell (activated T cell or

Treg

) Slide14

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The B7:CD28 familiesAbbas, Lichtman and Pillai. Cellular and Molecular Immunology, 8

th edition, 2014 Slide15

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Major functions of selected B7-CD28 family members

CD28-B7:

initiation of immune responses

ICOS-ICOS-L:

T cell help in germinal center reactions (antibody

responses)

CTLA-

4-B7:

inhibits early T cell responses in lymphoid organs

PD-1:PD-L1,2:

inhibits

effector

T cell responses in peripheral tissues

Activation

Inhibition Slide16

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Blocking CTLA-4 promotes tumor rejection: CTLA-4 limits immune responses to tumors

Administration of antibody that blocks CTLA-4 in

tumor-bearing

mouse leads to tumor regression Slide17

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The PD-1 inhibitory pathwayPD-1 recognizes two widely expressed ligands (PD-L1, PD-L2)

Knockout of PD-1 leads to autoimmune disease (less severe than CTLA-4-KO)Role of PD-1 in T cell suppression in chronic infections, tumors?Slide18

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Naïve CD8+

T cells

Effector

T cells

Memory T cells: enhanced antiviral responses

Exhausted T cells: inability to respond to virus

(expression of inhibitory receptors, e.g. CTLA-4, PD-1)

Virus

Acute infection:

c

learance of virus

Chronic infection:

p

ersistence of virus

T cell “exhaustion” in chronic viral infections Slide19

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Actions of PD-1

PD-1 attenuates TCR signaling in responding T cellsLimits harmful consequences of chronic stimulation with persistent antigen (self, tumors, chronic viral infections)

Greater role in CD8 than in CD4 T cells

Also expressed on follicular helper T cells; function? Slide20

Checkpoint blockade for cancer

i

mmunotherapy

Ribas

A. N

Engl

J Med 2012;366:2517-2519.

e.g.

ipilimumab

Slide21

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Ribas

A. N

Engl

J Med 2012;366:2517-2519.

e

.g.

n

ivolumab

,

pembrolizumab

e.g.

ipilimumab

Checkpoint blockade for cancer

i

mmunotherapySlide22

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Risks of blocking CTLA-4 or PD-1

Blocking a mechanism of self-tolerance leads to: Slide23

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Risks of blocking CTLA-4 or PD-1

Blocking a mechanism of self-tolerance leads to:

Autoimmune reactions (a new cottage industry for

clinicians

?)

Colitis and dermatitis are common

Vitiligo

,

Endocrinopathies

, hepatitis less common but described

Severity of adverse effects has to be balanced against potential for treating serious cancers

Less severe with anti-PD1 antibodySlide24

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Regulatory T cells Abbas, Lichtman

and Pillai. Cellular and Molecular Immunology, 8th edition, 2014, Elsevier Slide25

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Properties of regulatory T cells Phenotype: CD4+, high IL-2 receptor (CD25), low IL-7 receptor, Foxp3 transcription factor; other markersEssential features of stable Tregs

: Foxp3 expression: requires demethylated non-coding CNS2 sequence in promoter CD25 (IL-2Ra) expression: IL-2 is a necessary survival factor

CTLA-4 expression: required for suppressive function of most Tregs

(Inability to produce IL-2)

Take home messagesSlide26

The significance of Foxp3+

TregsGenetic evidence: Foxp3 mutations --> autoimmune disease (IPEX); in mice, disease can be corrected by providing normal Foxp3+ cells Do defects in Foxp3+ Tregs

or resistance to Treg-mediated suppression contribute to common autoimmune diseases? Inconsistent and variable data26Slide27

Mechanisms of action of Foxp3+

TregsCTLA-4 on Tregs removes B7 on APCs, reduces CD28 engagement and T cell activation Genetic deletion of CTLA-4 in Foxp3+ cells results in severe systemic autoimmunity and lymphoproliferation

Inhibitory cytokines produced by Tregs (TGF-b, IL-10, others?) suppress immune responses (DCs, Macs, T cells) IL-10 deletion in Foxp3+ cells results in colitis

IL-10 is also produced by Foxp3- cells Consumption of IL-2

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Regulatory T cellsExplosion of information about the generation, properties, functions and significance of these cellsWill cellular therapy with ex vivo expanded Treg become a reality?Therapeutic goal: induction or activation of Treg in immune diseases

Take home messages Slide29

The therapeutic potential of regulatory T lymphocytes

Cell transfer of

autologous

Tregs

to suppress immune responses

Grow up patient’s

Tregs

ex vivo

Ongoing clinical trials in graft rejection, T1D show

it is safe

In

one study of liver

Tx

, single infusion of

Tregs

resulted in tolerance (withdrawal of immunosuppression) in 7/10 patients (

vs

~10% historically)

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Functions of Interleukin-2: the dogma Slide31

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The unexpected biology of IL-2Interleukin-2 is the prototypic T cell growth factor (TCGF), required for initiating clonal expansion of T cells in response to antigen

BUT: knockout of IL-2 or the a or b chain of the IL-2R results not in immune deficiency but in systemic autoimmunity and lymphoproliferationSlide32

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Dual roles of IL-2 in T cell responsesSurprising conclusion from knockout mice: the non-redundant

function of IL-2 is in controlling immune responses

Take home messages Slide33

Differential effects of IL-2 on

Teff vs Treg

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Pathogenesis of

autoimmunity35Slide36

Therapy of immune disorders: rational approaches target lymphocyte activation and subsequent inflammation

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Autoimmune diseasesExperimental models are revealing pathways of immune regulation

But experimental animals are often inadequate models of human diseases Improving technologies for human genetic and phenotypic analyses are enabling studies of patients Challenges:

Defining which mechanisms of immune tolerance fail in different autoimmune diseases

Using

this

knowledge to develop therapies

Take home messages Slide38

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The landscape of T cell activating and inhibitory receptors: More to come?

TIGIT