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AD2 > T Lymphocytes > Flashcards

T Lymphocytes Flashcards

1
Q

What receptor(s) do mature T-cells express?

A

T-cell receptor (TCR)
CD8/CD4 co-receptor

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2
Q

What are the roles of the T-cell receptors?

A

TCR - pMHC recognition
CD4/CD8 - enhances sensitivity

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3
Q

Describe the structure of the T-cell receptor

A

T-cell receptors (TCRs) are made up of 2 transmembrane chains (alpha & beta)
Each chain is anchored in the membrane
Each chain contains a variable (V) & constant (C) region
TCRs bind to peptide binding platform of MHC & mediate pMHC recognition

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4
Q

What are the pros & cons of TCR degeneracy/crossreactivity?

A

Pros - effective immunity
Cons - pathogenesis of disease (eg immunological basis of autoimmunity & transplant rejection)

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5
Q

What are the 3 stages of T-cell activation by antigen presenting cells (APCs)?

A
  1. ACTIVATION
    -TCR & co-receptors (CD4/CD8) bind to foreign pMHC (on APC surface)
  2. SURVIVAL
    -co-stimulatory signal
    -delivered by same APC
    -CD28 on the T-cell binds to B7 molecules on APC
  3. DIFFERENTIATION
    -APC produces cytokines which influence pathway of differentiation & produce different subsets of effector T-cells that carry out different effector functions (CD4 T-cells in particular)
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6
Q

How does the engagement of TCR with specific pMHC trigger a cascade of signalling events that lead to T-cell activation?

A
  1. TCR is expressed in association with the CD3 complex
  2. TCR/pMHC interaction results in phosphorylation of the ITAMs (immunoreceptor tyrosine-based activation motifs) in several CD3 chains
  3. Phosphorylation of CD3 is mediated by Lck (protein kinase)
  4. Phosphorylated ITAMs recruit & activate ZAP70 which triggers a cascade of signalling
  5. T-cell signalling events lead to the activation of transcription factors in the nucleus, which results in proliferation & T-cell effector function
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7
Q

How do T-cells undergo clonal proliferation & differentiation following T-cell activation?

A
  1. T-cells undergo a physical transformation from a small lymphocyte into a lymphoblast
  2. Activated T-cells start to secrete cytokines & express cytokine receptors (IL-2 autocrine growth factor)
  3. The activated T-cell starts to divide which generates lots of T-cells with the same TCR
  4. Most become “effector cells”, but some also become “memory cells” which are responsible for immunological memory
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8
Q

How is TCR diversity generated?

A

-TCR repertoire is generated by a process called ‘somatic recombination’
-Involved rearranging genes that encode parts of the complete alpha & beta chains
-The TCR alpha locus = variable (V𝛼), joining (J𝛼), constant (C𝛼) gene segments
-The TCR beta locus = variable (V𝛽), joining (J𝛽), constant (C𝛽) gene segments

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9
Q

Describe the process of thymic maturation of T-cells

A
  1. Migration from cortex to medulla
  2. Differentiation to express a TCR with either CD4 or CD8
  3. Positive selection of TCRs that can interact with pMHC complexes
  4. Apoptosis of TCRs that interact with high affinity for self pMHC
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10
Q

What is the function of Tʜ1 cells?(helper)

A

Activate macrophages enabling destruction of intracellular organisms
Stimulate cytotoxic effector cells (CD8 T-cells & NK cells)

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11
Q

What is the function of Tʜ2 cells?

A

Major role in providing B-cell help to differentiate into plasma cells which secrete antibody (IgG, IgA or IgE)

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12
Q

What is the function of Tʜ17 cells?

A

Recruit neutrophils to sites of infection
Essential in response to fungi

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13
Q

What is the function of T𝖥ʜ cells?(follicular helper)

A

Reside in lymphoid follicles
Important for the formation &maintenance of germinal centres
Important in the regulation of B-cell differentiation into plasma cells

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14
Q

Describe the relationship between Tʜ1 & Tʜ2 responses

A

Immune deviation
Mutually agonistic
Tʜ1 cells produce IFN𝞬 (interferon), which inhibits Tʜ2 cells = cytotoxic cell mediated immunity
Tʜ2 cells produce IL-4 & IL-13, which inhibit Tʜ1 cells = humoral immunity

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15
Q

What are CD8 cytotoxic T-cells?

A

T-cells expressing CD8 differentiate into CD8 cytotoxic cells
CD8 T-cells kill their target cells on recognition of specific pMHCI
Important for immunity against intracellular infection (viruses, bacteria, fungi)
Capable of killing cancerous cells
Have specialised lysosomes that contain cytotoxic proteins (perforin, granzymes, granulysin)

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16
Q

What is the purpose of perforin?

A

Forms pores in the cell membrane causing cell lysis

17
Q

What is the purpose of granzymes?

A

Enter cells & stimulate apoptosis

18
Q

What happens after the cytotoxic (CD8) T-cell recognises its target cell?

A
  1. Cytotoxic (CD8) T-cell forms a close adhesion to the target cell
  2. Target cell & cytotoxic cells form membrane interdigitations & intercellular ‘tight junctions’
  3. This forms a contained microenvironment in the narrow space between the cells
  4. Cytotoxic (CD8) T-cell granules polarise towards junction with target cell
  5. Granules released at site of cell contact
19
Q

What is the role of Memory T-cells?

A

Immunological memory
-‘remembers’ antigens it’s previously responded to
-mounts a more potent ‘secondary’ immune response
-express different cell surface markers
-long lived

20
Q

What is the purpose of Natural Killer (NK) cells?

A

-When viruses infect cells, they produce IFN-𝛼 (interferon)
This cytokine activates NK cells to kill the virus-infected cell
Widely distributed around the body

21
Q

How do natural killer cells work?

A

Killer cell immunoglobulin-like receptors (KIRs) form activatory & inhibitory receptors
Inhibitory receptor bind with MHCI on target cell
Granules in NK cell contain perforin (damages cell membrane) & granzymes (stimulate apoptosis)
Granules released to induce apoptosis of virally infected cells and tumour cells
MHCI altered (viruses) or made absent (tumours)

22
Q

What are the disadvantages of T-cell therapy?

A

Need to improve basic understanding of immune system before it can be further developed

23
Q

What are the advantages of T-cell therapy?

A

T-cells have a potent ability to kill infected cells (esp. useful in viral infections)
T-cells have a potent ability to kill cancerous cells
T-cells can regulate the immune response (useful in autoimmunity & graft rejection)
T-cell therapy may have a long lived effect (may help prevent cancer relapses)

24
Q

How are T-cells genetically engineered to enhance their activity?

A
  1. Isolate T-cells from blood & culture in vitro with cytokines (eg IL-2)
  2. T-cells are genetically modified using vectors that encode genes for receptors or molecules that enhance responses to cancer cells
  3. Most common vectors = 𝞬-retroviruses & lentiviruses engineered to be replication incompetent by the removal of genes that encode vital proteins
  4. Genes of interest are incorporated in the genome of T-cells
25
Q

What are the advantages of genetically engineering T-cells to express cancer specific TCR’s?

A

It generates large numbers of cancer-specific CD8 T-cells in a very short space of time

26
Q

What are the disadvantages of genetically engineering T-cells to express cancer specific TCR’s?

A

-Must identify a suitable MHCI restricted tumour rejection antigen
-Must isolate a tumour specific TCR (very challenging)
-Therapy is restricted by a specific MHCI, so can only be used in a subset of patients

AD2 (39 decks)

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