Ch12: Co-evolution of innate & adaptive immunity

NK cells

• Release cytotoxic proteins (perforin, and granzyme)

  • Induce apoptosis and death of virus infected and cancer cells

  • Maintain inflammation

• recruited to infected tissue by the IL-12 (secreted by macrophages after recognzing a PAM)

  • o   NK cells have an IL-12 receptor. Binding makes them active → they start producing interferon gamma (INF-g)

    o   The INF-g will then reactivate/activate the macrophage further → The macrophage can degrade the pathogen better that it has been opsonizing

  • (IL-12 and INF are inflammatory)

• They kill virus-infected cells, cancer cells, cells with low or missing MHC-I proteins, cells emitting abnormal activating signals.

Why do NK cells belong to innate immunity?

• Their receptors are not antigen-specific (receptors do not undergo gene (VD-J) rearrangement)

  • They do not have an enormous amount of different receptors like B and T cells

  • NK cells can both having activating receptors and inhibiting receptors

• Act very fast upon infection “ready-to go” state

  • Adaptive immunity is much slower; needs antigen transport to the lymph nodes, which takes longer

• NK cell responses have a bit of memory → Virus specific cells remain in the blood for a longer me.

• But: they belong to the lymphocyte lineage

  • The lymphocyte progenitors give raise to the B cells and T cells, but they also give rise to NK cells

  • All the other innate cells come from the monocyte progenitors

Activatie NK vs T cellen

• T-cellen moeten door een specifiek antigen geactiveerd worden terwijl NK-cellen vele activerende receptoren hebben.

• Hierdoor reageren vrijwel alle NK-cellen in een infectie en ze circuleren in een gedeeltelijk-geactiveerde staat zodat ze snel kunnen reageren.

• Ze hebben daarom ook inhiberende receptoren die liganden van gezond weefsel herkennen.

• Voor activatie van NK-cellen zijn twee of meer activerende receptoren nodig.

NK cel activatie

• Voor activatie van NK-cellen zijn twee of meer activerende receptoren nodig → verminderd de kans van NK cellen in afwezigheid van infectie

• tijdens een adaptief immuunrespons (wanneer IgG besschikbaar is) kunnen NK cellen geactiveerd worden door één receptor → FcγRIIIA (CD16a)

  • Bevestiging van een tweede receptor is niet nodig omdat het pathogeen-specifieke antilichaam bevestigt dat de infectie echt aanwezig is

Immunoglobulin-like receptors:

• er zijn specifieke receptoren op de NK cells die binden aan MHC-I molecules op gezonde cellen → inhibits cell activity en voorkomt autoimmmunity

• chromosoom 19

• Bevat KIRs: herkennen specifieke, variabele epitopen op HLA-A,B&C

  • kunnen activerend signaal geven: Inhibit NK cell ac vity by binding to MHC-I, preven ng healthy cells from being attacked

  • kunnen ook inhiberend signaal geven: Activate NK cells to kill unhealthy cells when there is a lack of MHC-I

KIRs

• op oppervlak van NK cellen en herkennen gezonde lichaamscellen

• op chromosoom 19

• herkennen specifieke, polymorfe varianten van klassieke MHC I moleculen

• 2 KIR haplotypen

  • A: inhiberend

  • B: activerend

• zeer polymorf; doordat KIR en MHC op andere chromosomen zitten en dus onafhankelijk overerven

• heel speicifiek

Lectin-like receptors:

• binden aan HLA-E (geconserveerd) en kijken naar de totale hoeveelheid MHC-I

• op chrom 12

• receptoren vertonen weinig genetische variatie tussen individuen

  • zorgt voor een algemeen en universeel immuunmechanisme

  • wel less specific

• CD94:NKG2A is een belangrijke receptor

Healthy cell

1. In a healthy cell, the classical MHC class I proteins (HLA-A-C) are synthesized in the ER, during which the leader sequence is cut from the protein

2. Peptides from the leader sequence bind specifically to HLA-E

3. Only then is HLA-E stable enough to travel to the cell surface

4. f there is an HLA-E molecule on the cell surface, then it means that this cell is making enough MHC

5. When the NK cell inspects this cell, the CD94:NKG2A-receptor binds to the HLA-E-complex

6. The signal coming from this is an inhibitory signal to an NK cell (=inactivation of the signalcomponent Vav)

7. The cytotoxic granules are blocked

8. NK cell leaves the place, because it believes it is an healthy cell

Virus infection:

1. Viruses or tumours often decrease the expression of HLA class I on the cell surface

2. On the cell surface there are no HLA-E molecules that present the signal peptides

3. CD94:NKG2A can not bind -> inhibiting signal stays off

4. The NK cells do not get the inhibitory signals

5. Other stress molecules (f.e. MYC molecules) are present
   »» these are monomorphic as well, which means that we all have the same molecules for this

6. The activating receptors of the NK cells recognize these stress molecules

7. The NK cells will not get inhibitory signals, but only activating signal

8. NK cell kills the cell

»» So even though we have all different HLA molecules, the signal peptide of the HLA molecules are always the same (homolog molecules), which means that with one single molecule we can tell to NK cells how much MHC is being made in the cell

CD94:NKG2A

NK cells use the CD94:NKG2A receptor to assess the amount of HLA-A, -B, and -C on a cell by measuring the quantity of HLA-E on the surface

• CD94, NKG2A and HLA-E exhibit little variation among populations → To compensate the limitations of this little variation there are other NK receptors that recognize the polymorphic HLA-A, -B, and -C (=KIRs)

NK-cel educatie

het proces waarin een ontwikkelende NK-cel leert om de eigen gezonde cellen van het lichaam te tolereren en gevoelig te worden voor het verlies van MHC klasse I op zieke cellen → zorgt ervoor dat elke NK-cel specifiek wordt 'afgesteld' op het unieke HLA-profiel van het eigen individu

• nodig omdat de genen voor inhiberende KIR-receptoren (op chromosoom 19) en de genen voor HLA-moleculen (op chromosoom 6) onafhankelijk van elkaar overerven
  
  

• Bovendien komen KIR-genen op een willekeurige, stochastische manier tot expressie op verschillende NK-cellen.
  
  

educatie van NK cellen

• nodig omdat KIRs en MHC niet op hetzelfde chromosoom liggen en daardoor geen linkage disequilibrium kunnen hebben

• vindt plaats in het beenmerg tijdens een laat stadium van de NK-ontwikkeling

1. eerst lectin like receptros tot expressie, dan KIRs

2. de NK-cel test of een inhiberende receptor (lectin of KIR) bindt aan een passend self-MHC-I molecule

3. a) Ja → inhiberende signaal naar binnen
   b) Nee → geen inhiberende signaal

4. a) de sterkte van het inhiberende signaal bepaalt hoe krachtig de NK cel later kan reageren
   b) cel blijft hyporesponsief: niet goed reageren op gezonde of zieke cellen

5. b) deze KIR moleculen worden gedownregulated

uterine Natural Killer-cellen (uNK cells)

• uNK cells interact with fetal extravillous trophoblast cells to provide the placenta with adequate blood supply

• Is only really important in humans, because our babies have big brains, which need a lot of blood supply (which also means that there are no animal studies for us to research this)

HLA of mother and father are the same (theory)

a.       When the mother gets pregnant, a blood supply from the mother to the fetus is needed. To have sufficient bloods supply we need some NK cell activation

b.       The mother’s uNK cells recognize a little bit of the trophoblast cells from the fetus

c.       uNK cells get activated and will cause a small cytotoxic response (en groeifactoren voor de formatie van nieuwe bloedvaten)

d.       A complecte evasion of the spiral arteries between the mother and fetus arises

e.       Enough blood flow from the mother and child

HLA of mother and father are the same (theory)

1.       When the mother gets pregnant, a blood supply from the mother to the fetus is needed. To have sufficient bloods supply we need some NK cell activation 

2.       If the HLA molecules of the mother and father are very similar to each other, then the NK cells of the mother would not really recognize the fetus as foreign and they will not get activated

3. An incomplete invasion arises → not enough blood transport from the mother to the fetus, because the NK cells do not make the blood flow possible

not enough or too much

• If there is not enough trophoblast invasion, then this results in pre-eclampsia

  • Not enough blood supply; the mother’s heart is working in overload to provide more and more blood, which results in high blood pressure. Baby is often taken out during the 7^th or 8^th month to save the mother

• If the mothers uNK cells get too active (=too deep placental invasion), this causes the development of babies that are too large for birth canal, and thus obstructed labour

  • The blood supply is very large and can cause temporary diabetes in the babies