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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
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)
Neutrophils
Galli et al Nature Immunology Reviews 2011
- Recruit immune cells- Inhibit acquired immune reactions
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
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
2
1
3
Acquired (>72h)* Antigen presentation (APCs)
* Lymphocyte interactions* Antibody production
* Memory
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 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
The B7 superfamilyBoth stimulatory and inhibitory co-receptors
T cellAPC
from Nature Reviews Immunology
T cell co-receptors or signal 2 can induce inhibition
eg. PD-1 transcription!
CTLA-4
PP2APP2ASHP2SHP2
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
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”