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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