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Immunology > Natural Born Killers: NK Cells and CD8+ T Lymphocytes > Flashcards

Natural Born Killers: NK Cells and CD8+ T Lymphocytes Flashcards

1
Q

How are CD8 T cells and NK cells similar?

A

Both Cytotoxic T cells and natural killer cells essentially do the same job but as part of different types of immunity

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2
Q

Which cell is a major part of the innate immune system?

A

NK cells: non-specific (or broadly specific), immediate response

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3
Q

Which immune cell is an integral part of the adaptive immune system?

A

T cells: highly-specific, delayed response`

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4
Q

Where do T cells and NK cells originate?

A

Both arise from common lymphoid progenitor cell

Both part of lymphocyte lineage

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5
Q

What is the role of cytotoxic CD8+ T cells?

A

We need cytotoxic cells as a means to destroy

  • Cells infected with bacteria, viruses or parasites
  • Tumour cells
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6
Q

What is the role of MHC Class I molecules?

A

MHC class I proteins are found at the cell surface and form a structure that holds antigenic peptides for surveillance by T cells

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7
Q

How are MHC I molecules recognised?

A

MHC-I = recognised by CD8+ cytotoxic T cells

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8
Q

How do MHC molecules aid pathogen recognition?

A

Intracellular proteins are presented at the cell surface by MHC class I

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9
Q

Which proteins are presented on MHC I molecules?

A

Proteins expressed within a cell (whether healthy, mutated or resulting from infection) are processed and presented on MHC class I proteins

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10
Q

Describe the structure of MHC I molecules

A

Humans: HLA-A, -B, -Ctwo polypeptides, non-covalently bound:

𝛂3 domain and ꞵ2 microglobulin provide support to peptide binding group on top
2 𝛂 helices at sides of groove and ꞵ sheet at the bottom forms base

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11
Q

Which cells express MHC Class I molecules?

A

all nucleated cells

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12
Q

Why don’t we see many pathogens mutating to avoid antigen presentation

A

MHC class I proteins are central to antiviral immune responses

  • Multiple genes (e.g. 2 copies each of HLA-A, B + C)
  • High genetic variability within these genes
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13
Q

Outline what enables MHC Class I variability

A

Polymorphisms in upper peptide-binding part of MHC protein - provide variation in the peptide binding groove

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14
Q

Where on the MHC molecule do pathogenic peptides bind?

A

Amino acids in the MHC peptide binding groove create pockets where the bound peptide can “anchor”

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15
Q

How do polymorphisms provide variation in MHC I molecules?

A

By substituting different amino acids, we get different charges (+ve/-ve) between MHCs, different sizes and shapes between pockets ⇒ different peptides bind to different MHC alleles

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16
Q

What substances do TCRs recognise?

A

TCR recognise two things

  • MHC protein itself (hence compatibility)
  • Antigenic peptide presented by MHC protein

TCR recognises both MHC protein and peptide antigen being presented by it

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17
Q

How does MHC structure allow T cel recognition?

A

Binds with a diagonal footprint that cuts across both alpha helices with the peptide in between - allows T cell recognition

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18
Q

WHy can CD8 and TCRs bind to MHC simultaneously?

A

Distant binding sites allow CD8 and TCR to bind MHC-I at the same time

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19
Q

What is the role of CD8 binding to MHC?

A

CD8 acts as a co-receptor for MHC-I, and is required for the T cell to make an effective response

20
Q

Where on the MHC I molecule do TCRs bind?

A

TCR binds to the α1α2 domains

21
Q

Which part of the MHC I molecule do CD8 peptides bind?

A

CD8 binds to the support domains (α3 and β2m) - very highly conserved region to ensure CD8 binding
- Similar situation for CD4 and MHC-II

22
Q

Outline how different viruses may subvert MHC functions

A

Microbes may subvert MHC upregulation by:

  • Inhibit MHC-I transcription (adenovirus)
  • Block TAP activity (HSV)
  • Retain MHC-I in endoplasmic reticulum (adenovirus, HCMV)
  • Target MHC-I for disposal from ER (HCMV)
  • Downregulate MHC-I from cell surface (HIV)
23
Q

What are NK cells?

A

Classical NK cells are large granular lymphocytes that are not T or B cells

24
Q

Describe the protein structures of classic NK cells

A
  • Don’t express TCR (CD3) or B cell receptor
  • Express cell surface marker CD56
  • CD3- CD56+
25
Q

What are the 2 major roles of NK cells

A

Cytotoxic functions and cytokine secretion

There are different populations of NK specialised more towards either function

Most are specialised for cytotoxic functions

26
Q

How do MHC I molecules recognise NK cells?

A

Killer Ig-like receptors (KIR) are innate immune receptors that regulate the activity of Natural Killer cells - their binding site is within the antigen presenting part of the MHC

27
Q

What is the function of KIR?

A

When KIR recognise MHC-I they inhibit NK cells from releasing lytic granules (-ve signal)

28
Q

Why do KIR inhibit NK cytotoxic functions?

A

Some viruses down-regulate MHC-I as a means to evade cytotoxic T cells, loss of MHC-I is also a common feature of tumour cells
Mechanism also protects healthy cells

29
Q

How odes a lack of MHC I molecules enable NK cytotoxic effects?

A

If a target cell does not express MHC-I then there is no KIR inhibition, lytic granules will be released to lyse the target
Known as “missing self”

30
Q

Where do KIR bind n MHC?

A

Inhibitory KIR bind to the same face of MHC-I as the T cell receptor
- recognise subsets of MHC-I alleles

31
Q

Describe the variation in KIR

A

KIR are also polymorphic, as well as being polymorphic individual KIR genes vary in their presence between individuals
Different MHC-I/KIR combinations show disease associations e.g. in HIV infection

32
Q

What is the role of natural Cytotoxicity receptors on NK cells?

A

These provide activating signals to NK cells, but are not well characterised (+ve signal)

33
Q

Describe the roles of different NCRs

A

NCR 1 binds viral hemagglutinin

NCR2 – binds a ligand expressed on tumor cells and upregulated by viral infection

Ligand for NCR3 is a stress induced protein

34
Q

How is NK Cell activity regulated?

A

NK cell activity is regulated by a balance between inhibitory signals (recognising MHCs) and activating signals from other receptors

35
Q

What is ADCC?

A

Antibody-Dependent Cell-Mediated Cytotoxicity is a Super activating signal for NK cells
- Fc receptors (CD16)

36
Q

Outline how Fc receptors on NK cells activate a lytic response

A
  1. Antibodies bind antigens on target cell surface
  2. Fc receptors on NK cells recognise bound antibodies
  3. Cross-linking of Fc receptrs signals NK cell to kill target cell
  4. Target cell dies by apoptosis
37
Q

How do Tumour cells evade immune responses?

A

Similar to many pathogens, tumor cells can escape the adaptive immune system, by downregulating the expression of MHC class I

  • makes them more susceptible to NK cells
38
Q

How do cytotoxic (T + NK) cells kill target cells?

A

NK cells and T cells carry granules filled with cytotoxic proteins

Release cytotoxic granules at site of contact with target cell
(must be directed in order to avoid damaging innocent bystander cells)

39
Q

Name 3 cytotoxic granules in CD8 T cells

A
  • Perforin
  • Granzymes
  • Granulysin
40
Q

What is the role of perforin?

A

Delivers contents of granules into cytoplasm of target cell

41
Q

How do granzymes cause cytotoxic effects?

A

Serine proteases

Activate apoptosis once inside target cell cytoplasm

42
Q

How does granulysin activate apoptosis?

A

Antimicrobial action causes apoptosis

43
Q

How do CD8 cells trigger apoptosis?

A

CD8 cells can trigger apoptosis of target through Fas/FasL protein interaction
- not cytotoxic granule dependent

44
Q

Describe the Fas/FasL interaction

A

Fas ligand (FasL) on T cells engages Fas on target cells to trigger apoptotic pathway

45
Q

What is the use of Fas/FasL apoptosis?

A

Fas/FasL triggered apoptosis is used to dispose of unwanted lymphocytes

46
Q

What is the consequence of loss of Fas?

A

Loss of Fas can result in autoimmune lymphoproliferative syndrome (ALPS) due to lack of removal of excess lymphocytes

Immunology (14 decks)

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