Natural born killers: NK cells and CD8+ T lymphocytes**

Question 1

State similarities between NK cells + Tc cells?

Answer 1

• Arise from common lymphoid progenitor cells + part of lymphocyte lineage
• Common Lymphoid progenitor cells: T cells (- CD8), Innate lymphoid cells ( -> Nk cells), B cells

Question 2

State the 2 roles of cytotoxic lymphocytes (NK + Tc)?

Answer 2

• Destroy infected + tumour cells, scan
• Target cell surface for changes in protein production

Question 3

Describe the adaptive cytotoxic lymphocyte?

Answer 3

• CD8 cytotoxic T cells
• CTL/CD8 T cells -> kill virally infected targets + infected cells -> controlled via T cell receptor recognition + CD8 as co-receptor -> Highly specific for antigen

Question 4

Describe the innate cytotoxic lymphocyte?

Answer 4

• NK cells -> kill virally infected targets + tumour cells -> controlled via balance of signals from different activating + inhibitory receptors on their surface -> Broad specifity for target cells (many)
• NK cells express a diverse combination of receptors
• Target many things - not just one specific antigen like CD8 cells

Question 5

Why do we need NK cells when we already have CD8 cells?

Answer 5

• Based of the principle that NK cells are formed first (as part of the innate and then later CD8 CTL cells come (as part of the adaptive response)
• Combat infection before T cell response develops
• Alternative system when evasion of CTL cell responses
• Additional mechanism for killing via AB recognition

Question 6

What infection is correlated with low NK cell activity?

Answer 6

Decrease NK cell (deficiency) -> severe disseminating herpes virus infection -> chickenpox, HCMV, HSV

Question 7

T cell recognition by MHC class I
Describe the role of MHC class I in antigen presentation?

Answer 7

• Based on primary role:
• Lymphocytes scanning a target cell surface need to detect changes in protein production inside that target cell
• MHC class I found at the target surface -> Form a structure that presents peptides at the cell surface for immune surveillance -> Recognised by CD8+ Tc cells

Question 8

Describe the presentation of intracellular proteins at the cell surface of MHC class I?

Answer 8

• Normal/mutated or viral Proteins expressed within cell -> processed + presented on MHC class I
• Virus infects cell -> V proteins synthesised in cytoplasm -> antigen processing to peptides in proteosome -> peptide transport to ER -> Peptide binds MHC + transported to cell surface -> MHC presents peptide at cell surface for recognition via T cell > kills

Question 9

Structure of MHC
Describe the structure of MHC class I?

Answer 9

Found on all nucleated cells
- 2 polypeptides, non-covalently bonded
- Alpha chain (polymorphic, glysolated + inserted in membrane) + beta-microglobulin (reverse of alpha)
- Structure: Peptide-binding cleft (Alpha-1, 2 (alpha helix), beta sheet) + b-2 microglobulin + alpha-3

Question 10

Describe the chromosomal location of the MHC and why its so highly polymorphic?

Answer 10

• MHC / human leucocyte antigen (HLA) gene complex - chromosome 6 -> 3 MHC class I (A, B,C) + 3 MHC class II -> highly polymorphic (Increased genetic variant)
• HLA polymorphism -> pathogen evolve to evade immunity -> MHC I variation (multiple genes) + increased genetic variation -> counteracts this

Question 11

State the location of MHC polymorphism within its structure?

Answer 11

Upper part of peptide binding groove

Question 12

How does MHC polymorphism relate to binding of antigenic peptides?

Answer 12

• variants arise via changes in PBG -> AA in MHC PBG create pockets where the bound peptide “anchor” in MHC
• Variations between different MHC alleles -> Variations in size, charge and location of pockets -> Variations in type of peptides that can anchor within the pockets

Question 13

Describe the central role of MHC-I proteins?

Answer 13

• Distinguish self via recogniton of right version of MHC
• Distingiush self from non-self -> via TCR recognition of MHC (compatability) + antigenic peptide (presented by MHC)

Question 14

Describe the T cell receptor recognition process of MHC and how they bind?

Answer 14

• TC recognises MHC + peptide presented -> binds with diagonal footprint that cuts across both alpha helices with peptide in between -> TCR binds to alpha-1alpha-2 domain
• CD8 (co-receptor) -> required for T cell response -> binds supports domain (alpha 3 + beta-2m) of MHC -> conserved regions
• CD8 + TCR binding sites are distant

Question 15

NK cell recognition
Describe examples of viruses with their methods on how pathogen subvert presentation by MHC-I?

Answer 15

• Inhibit MHC-I transcription (adenovirus)
• Block peptide transport into ER (HSV)
• Retain MHC-I in ER (adenovirus, HCMV)
• Target MHC-I for disposal from ER (HCMV)
• Down regulate MHC-I from cell surface (HIV)

Question 16

Killer Ig-like receptors (KIR)
Describe the function of KIR?

Answer 16

• KIR (killer Ig-like receptors) on NK cells -> recognise MHC-I -> inhibit NK -> stop release of lytic granlues
• If target doesn’t express MHC-I -> ‘missing self’ mechanism -> No KIR inhibition of NK -> release of lytic granules -> target lysed

Question 17

Describe features of KIR?

Answer 17

• Inhibitory KIR bind to the same face of MHC-I as TCR -> recognise subsets of MHC-I alleles
• NK cell expresses multiple KIR -> KIR genes are polymorphic -> Each KIR has different target of MHC alleles -> different disease associations

Question 18

Natural cytotoxicity receptors
What is the purpose of natural cytotoxcity receptors on NK cells and state 3 examples with their function?

Answer 18

• Provide activating signals on NK cells
• Ligands -> NKp46 (bind viral haemagglutinin), NKp44 (bind ligand expressed on tumour cell + upregulated by viral infection), NKp30 (stress induced protein)

Question 19

Antibody-dependent cell-mediated cytotoxicity (ADCC)
Why do NK cells kill tumour cells?

Answer 19

Tumour cells -> escape adaptive -> decrease expression of MHC I -> susceptible to NK cells

Question 20

Describe the Antibody-dependent cell-mediated cytotoxicity (ADCC) mechanism for NK cells?

Answer 20

• NK cells express a receptor that recognizes the Fc portion of AB -> This receptor delivers a strong
• Activating signal when it recognizes AB bound to cell surface -> lysis of the target cell

Question 21

Killing mechanisms - Cytotoxic granules
Describe the mechanism of lysis? VD

Answer 21

NK + Tc cells carry granules filled with cytotoxic proteins (perforin, granzymes + granulysin) -> granules released at site of contact with target cell -> Release is targeted in order to avoid damaging innocent cells

Question 22

Describe the immunological synapse and how this allows for release of granules?

Answer 22

• At site of cell-cell contact -> TCR + co-receptors cluster (redistribute) -> T cell polarises to release effector molecules (CKs) at point of contact

Question 23

Describe what interaction can also trigger apoptosis using CD8 cells? VD

Answer 23

• Fas/FasL interaction via PC-8 -> Fas ligand (FasL) on T cells engages Fas on target cells to trigger apoptotic pathway -> disposes unwanted/excess lymphocytes (Tc) -> Decreased Fas = autoimmune lymphoproliferative syndrome -> slower than cytotoxic granules (2 hour lag time)

Question 24

Comparison of Tc + NK cells

Answer 24

VD