Basic Immunology

K Leandersson 2015Cancer immunology

Self/ Non-self recognition

Specif icity

Diversity

Self / Non-self restriction

� Transplantation studies Medawar and Burnet, Nobel prize 1960

� Immunity to non-self is acquired

� The development and action of immune cells is tightly controlled - ”Tolerance” to self

Specif icity

Diversity

What is the immune system?

1) Polymorphonuclearcells - PMNs (Neutrophils, Basophils, Eosinophils, Mastcells)

2) Lymphocytes

3) APCs- Monocytes (in blood) or Macrophages (in tssues) / Dendritc cells

Leukocytes

2

1

3

An immune response is divided into two parts

Immediate1. Barrier

2. Cell mediated

Early (4-72h)Inf lammation

Acquired (>72h)1. Cell mediated

2. Lymphocyte interactions 3. Antibody production

4. Memory

Non-specif ic (Innate) Specif ic (Acquired)

Innate immunity

Targets for the innate immune response

Parasites

Bacteria

Fungi

Damaged or dead cells

Targets for the innate immune response

Damaged or dead cells

Wound healing mechanisms

Innate immune response

Resident phagocytes

Neutrophil

Mast cell

Macrophage

Immune cell recruitment

MacrophageNeutrophil

Neutrophils

Galli et al Nature Immunology Reviews 2011

- Recruit immune cells- Inhibit acquired immune reactions

Cell inf iltration in a wound

Macrophage recruitment

1) Microenvironment2) Time

Macrophage plasticity

Clear infectionsTissue injury

ImmunosuppressionTissue repairInvasion

Pattern recognition receptors (PRRs)

NF B!

The macrophage in inf lammationNF B induced target genes

PRRs in Sterile inf lammation

PAMPs – pathogen associated molecular pattern (pathogen molecules (eg. LPS))DAMPs – danger associated molecular pattern (endogenous molecules/proteins eg. HSP)

Angiogenesis

Cell recruitment

PhagocytosisAnt-microbial functon

Wound debridement

Matrix synthesis regulaton

- Oxygen radicals- NO

- Phagocytosis-Enzymes (collagenase, elastase)

-Growth factors (TGF , EGF, PDFG)-Cytokines (TNF , IL-1, IFN )-Enzymes (collagenase, arginase)-Prostaglandins (PGE2)

-Growth factors (PDGF, TGF , EGF, IGF)-Cytokines (TNF , IL-1, IL-6)-Fibronectin

-Growth factors (bFGF, VEGF)-Cytokines (TNF )

Macrophage functions

Innate immunityLymphocytes

Natural Killer (NK) cells

NK cell

NK cells kill cells lacking MHC I molecules (via Killer Immunologlobulin-like receptors KIRs)

TumorcellNK cell

KIRs

NKG2D MICA

X Y

NK cells can kill cancer cells

BUT

Innate immunity rarely clears the infection completely and does not

lead to immunity…

Innate immunity is a f irst line of defence

Adaptive immunity

Adaptive immunity

2

1

3

Acquired (>72h)* Antigen presentation (APCs)

* Lymphocyte interactions* Antibody production

* Memory

Antigen presenting cells

Antigen presenting cells (APC)

Macrophages, dendritic cells and B cells

-Phagocytose, process and present ”invaders”- Antigens

-Bridge the Innate Acquired immune response

Antigens

� Foreign substances capable of inducing a specif ic immune response

� Non-self (or mutated self)

� Presented as peptides on MHC/HLA molecules on APCs

Lymphocytes

2

1

3

Acquired (>72h)* Antigen presentation (APCs)* Lymphocyte interactions

* Antibody production* Memory

T Cells

T cells• Helper T cells (TH)

• Cytotoxic T cells (CTL)

•Tregs

NKT cells

T cellsBorderline innate

immunity (low diversity)

Th

Tc NKT

TTCR CD4+

TCR CD8+

TCR CD4/8+/-

TCR NK1.1+ CD4/8+/-

Canonical TCRs

Treg

TCR CD4+

CD25+FoxP3+

T cell activation

Antigen presentation

CLP

Naïve Tc cell

CD8+ TCR T cell

Clonal expansio

nCTL

Cytotoxic TCR CD8+

Virus infected

cell

ThymusThymus

CLP

Th Helper T cell TCR CD4+

Cytokines

Activation induced cell death (AICD):-Perforin-Granzyme-Fas:FasL-=> Apoptosis

T helper Cells

McKee et al. BMC Biology 2010

Th

T cell activation

Antigen presentation

CLP

Naive Tc cell

CD8+ TCR T cell

Clonal expansio

nCTL

Cytotoxic TCR CD8+

3. Cytokines

Virus infected

cell

ThymusThymus

CLP

Th Helper T cell TCR CD4+

Cytokines

1. MHC: Antigen complex

2. Co-receptorsignal

Adapted and modif ied from De Koker et al. Chem soc rev 2011

Antigen

The 3-signal modelThe 3-signal modelTo become activated a T cell needs three signalsTo become activated a T cell needs three signals

T cell co-receptors

Signal 2

The B7 superfamilyBoth stimulatory and inhibitory co-receptors

T cellAPC

from Nature Reviews Immunology

T cell co-receptors Signal 2 can induce co-stimulation

eg. IL-2 transcription!

T cell co-receptors or signal 2 can induce inhibition

eg. PD-1 transcription!

CTLA-4

PP2APP2ASHP2SHP2

T cell co-receptors

Signal 2 regulates the outcome of activity

B cell activation

Antigen presentation

CLP

Clonal expansio

n

Activated B cell(Plasma cells)

NaïveB cell

B

Th Helper T cell TCR CD4+

Cytokines

2. Signal 2 isCD40:CD40L

Unconventional T Cells

T cells• Helper T cells (TH)

• Cytotoxic T cells (CTL)

•Tregs

NKT cells

T cellsBorderline innate

immunity (low diversity)

Th

Treg

Tc NKT

TTCR CD4+

TCR CD8+

TCR CD4+

CD25+FoxP3+

TCR CD4/8+/-

TCR NK1.1+ CD4/8+/-

Canonical TCRs

Common T Cell & NKT cell functions

1) Unconventional TCR recognition 2) Antibody dependent cell-mediated cytotoxicity (ADCC)3) NK cell receptor mediated killing (eg NKG2D:MICA/B)

IFN

Regulation of the immune system

Treg

Why are cancer cells not deleted?

1) Tolerance induction - Self!

2) Regulatory mechanisms

Tolerance induction

• Active state of specif ic immunologic nonresponsiveness

• Tolerance is learned (acquired)

• Self-reactive B and T cells are deleted in the bone marrow and thymus (Central tolerance) and in the periphery (Peripheral tolerance)

• Self-reactive lymphocytes that are not deleted become anergic (functionally non-responsive)

• Regulatory mechanisms

Immunoregulatory mechanisms

•Regulation by antigens: Antigen dose

•Lack of co-stimulation or downregulation of MHC

•Cytokines (eg IL10 and TGF )

•Co-receptors: CTLA-4 and PD1 are inhibitory co-receptors on T cells

(eg. B7:CD28 activating; B7:CTLA-4 inhibiting)

•Regulatory T cells ”Tregs” can inhibit a specif ic immune response

Treg

Regulatory T cells functionsRegulatory T cells functionsInhibit other T cellsInhibit other T cells

Soluble factors

Cell contact

Passive mechanisms

Tolerance imbalance

1) Immature DCs Mature DCs

IMBALANCE

2) Inhibitory Coreceptor Stimulatory Coreceptor

IMBALANCE

3) Regulatory T cells Conventional T cells

IMBALANCE

4) Myeloid suppressor cells Myeloid cells

IMBALANCE

InfammatoryInduce infammaton

Eradicate non-self

Ant-InfammatoryStop the infammaton

Induce wound healing mechanismsInvasion

Immature DCMature DC

MM

Adopted and modif ied from Bhardwaj JCI 2007

”A wound that never heals”

Imbalance in immunological self tolerance…

Thank you!

IDO

T cell

Cancer cell T reg

APCCTLA-4CD28

TCRMHC

B7 family

CD40L CD40

PD-1

PD-1L

CTLA-4

CD25

NK cells

• Innate immunity– (non-specif ic killing)

• Recognizes loss of MHC expression (virus and cancer cells, transplants)

• Does not require activation

• Kills via cytotoxicity and death receptors

T cell B cell NK cellLymphocyte