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Cell-mediated immunity Flashcards

1
Q

what happens to T cells in the thymus?

A

antigen-independent rearrangement of TCR genes
- after thymic selection, “naïve” T cells expressing T cell receptor and CD4/CD8 are generated.
- Selection process is stringent – only 5% of T cells will leave the thymus

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2
Q

what happens to T cells in secondary lymphoid tissue?

A

antigen-dependent T cell activation:
- T cells activated by antigen-presenting cells displaying MHCI/MHCII + peptide differentiate into “effector” T helper or T cytotoxic cells.
- Generate cytokines or directly kill infected host cells.

Effector T cells are what contribute to cell-mediated immunity

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3
Q

what signals are involved in the production of effector T cells:

A

signal 1: Naïve T cell will enter lymphoid tissue and recognition of MHC + peptide + co-receptor (CD4/8)
- T cell recognises antigen and becomes activated

signal 2: Recognition of co-stimulatory molecule(s)
- CD28 and B7 are both members of human immunoglobulin gene superfamily
- T cells exposed to signal 1 in the absence of signal 2 become unresponsive/tolerised

signal 3: Cytokines convert activated T cells into different subsets = signal 3
- T cells will develop into a certain subset relevant to the infection type

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4
Q

what co-stimulatory molecule is important in activation of T cells?

A

One of the best characterised is B7 expressed by dendritic cells, macrophages, B cells (APCs)

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5
Q

how does B7 act to stimulate T cells?

A
  • B7 on APC interacts with CD28 on surface of T cell, inducing expression of IL-2 and IL-2 receptor by the T cell – auto-stimulatory
    -IL-2 acts in autocrine fashion on CD4+ve T helper cells; also required for CD8+ve cytotoxic T cell activation
  • Other cytokines direct T cell differentiation into different subsets of CD4+ve T effector cells (Signal 3)
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6
Q

how are CD4+ve T cells organised into subsets?

A

they differ in the cytokines that they produce
- Different cytokines induce activated “naïve” T helper cells (a.k.a. TH0 cells) to differentiate into various T cell effector subsets.

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7
Q

what triggers TH0 cells to differentiate into T cell subsets?

A

TH0 is the naïve T cell which receives signal 3 cytokines to differentiate into a subset of T helper cell
- Signal 3: cytokines made by antigen-presenting cell vary depending on type of infection

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8
Q

what are the different T cell subsets?

A

TH1, TH2, TH17, TFH, TREG

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9
Q

what distinguishes T cell subsets from one another? why is this important?

A

The T cell subsets differ in the types of cytokines they make and their role in immune responses
- Helps ensure pathogen appropriate immunity – fine tunes the immune response

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10
Q

what triggers transition of TH0 to TH1?

A

cytokines IL-12 and IFN-gamma

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11
Q

what is the role of TH1 cells?

A
  • produce IL-2 (autocrine), IFN-gamma and TNF
  • Most abundant T helper subset in blood
  • Activate macrophages to induce inflammation (classic cell-mediated immunity)
  • Important in intracellular infections and indirectly in extracellular infections via IgG
  • Induce B cells to make IgG1 and IgG3 opsonising antibodies and can activate complement
  • Important for development of cytotoxic T cells = IL-2
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12
Q

what triggers transition from TH0 to TH2?

A

cytokine IL-4

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13
Q

what is the role of TH2 cells?

A
  • produce IL-4, IL-5 and IL-13
  • Activate eosinophils and mast cells
  • Important in helminth infections and allergy
  • IL-4 and IL-13 induce B cells to make IgE – promote mast cell degranulation and inflammation
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14
Q

what triggers transition from TH0 to TH17?

A

cytokines TGF-beta and IL-6

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15
Q

what is the role TH17 cells?

A
  • Produce IL-17 and IL-22
  • Activates epithelial cells, fibroblasts, found near mucosal surfaces
  • Act at mucosal surfaces to promote inflammation = recruit neutrophils
  • Important in fungal and extracellular bacterial infections
  • Role in autoimmune disease e.g. Crohn’s disease
  • Recruit neutrophils to sites of infection
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16
Q

what triggers transition from TH0 to TFH?

A

cytokine IL-6

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17
Q

what are lymphoid follicles?

A
  • Lymph nodes are divided into areas predominantly T cells and follicles where B cells differentiate into plasma cells
  • Follicular T cells reside in these follicles
18
Q

what is the role of T follicular helper cells?

A
  • Produce IL-21
  • Found in lymphoid follicles
  • Help naïve B cells differentiate into plasma cells and memory cells
  • Promote somatic hypermutation and class switching
  • Cytokines switch on AID enzyme
19
Q

what does TFH function require?

A

Contact-dependent – TFH requires interaction between co-stimulatory molecules CD154 and CD40 to enable B cell and T cell to touch
- This occurs in the follicles of the lymph nodes

20
Q

what determines the immunoglobulin class that TFH cells induce B cells to make?

A

Depending on type of infection, different cytokines are produced by TFH cells:
- Causes activation of appropriate innate responses to help body deal with infection
- B cells promoted to differentiate into cells which make IgG, IgE, IgA

21
Q

what causes the transition from TH0 to Treg?

A

cytokine TGF-beta

22
Q

what is the role of Treg cells?

A
  • Heterogeneous group which suppresses immune responses
  • Induced Tregs suppress T cell subsets
23
Q

what are the features and roles of natural Treg cells?

A
  • develop in thymus
  • recognise MHC+self-peptide
  • suppress via contact, IL-10 and TGF-beta
  • target dendritic cells, effector T cells
  • suppress autoreactive T cells
24
Q

what are the features and roles of induced Treg cells?

A
  • develop in periphery mucosal lymphoid tissue
  • recognise MHC + non-self peptide
  • suppress via IL-10 and TGF-beta
  • target effector T cells
  • causes downregulation of mucosal immunity, inflammatory responses
25
how do cytotoxic T cells induce target cells to undergo apoptosis?
1. Proteases (granzymes) from cytotoxic T cell enter target cell via perforin channel and trigger caspase cascade 2. fas ligand on surface of cytotoxic T cell induces clustering of fas (“death receptor”) on target cell and triggers caspase cascade to induce apoptosis - Fas pathway may be important in downregulating immune responses - Fas is normally distributed evenly on target cell, and when interacting with cytotoxic T cell it clusters
26
is killing by cytotoxic T cells effective?
Yes: - SPECIFIC - only infected cells bearing antigen are killed - EFFICIENT - granzymes are pre-formed; a single cytotoxic T cell can kill 100s of infected targets - “CLEAN” – enzymes formed during apoptosis degrade viral DNA and destroy non-viral pathogens. Apoptotic cells are taken up by phagocytes
27
what cytokines can cytotoxic T cells produce?
IFN-gamma TNF-alpha
28
what causes allergy and autoimmune disease?
inappropriate activation of T cell subsets
29
what is allergy? how is it caused?
- Disease following an immune response to innocuous antigen (ALLERGEN). - Mostly IgE-mediated a.k.a. Type I Hypersensitivity
30
what are the different hypotheses on why allergy is increasing in developed countries?
The hygiene hypothesis Counter regulation/'old friends' hypothesis
31
what is the hygiene hypothesis of allergy?
- Children brought up on farms, or from large families, are less prone to develop allergy. - Early, repeated childhood infections may be protective. - Insufficient exposure to certain types of infection (“dirt”) skews TH1/TH2 balance towards TH2? - BUT there is a negative correlation between helminth infections and allergic disease.
32
what is the counter regulation/old friends hypothesis of allergy?
- Childhood infection protects against allergy by promoting IL-10 production: (Treg ↑, TH1 ↓ and TH2↓) - Infection with microbes or larger parasites plays a critical role in driving immunoregulation e.g. promotes formation of Treg, IL-10 - Human immune system and “Old friends” co-evolved - May also explain rise in autoimmune disease in the west (TH1/TH17-driven) - Infections are needed to promote Tregs to dampen down the immune response
33
what are gamma-delta T cells?
- 5% of T cells express gamma-delta chains with no CD4/CD8 - Generated earlier in development than αβ T cells – these are the T cells that we make first - Often found at mucosal epithelium lining mucous surfaces - Less diverse, recognise a broader range of antigens (including lipids, phosphorylated antigens, DAMPs e.g. heat shock proteins) - Do not appear to require processing or presentation by MHCI/II – independent of antigen presentation
34
what is the role of gamma-delta T cells?
- Can make cytokines e.g. proinflammatory IL-17, IFN-γ, TNF but also cytotoxic. - Can act as antigen presenting cells to αβ T cells. - Role in various intracellular bacterial, viral and parasitic infections (mycobacteria, flu, HIV, malaria) and also in cancer (not MHC restricted) - May “bridge” innate and adaptive immunity
35
why are immune responses terminated?
Once an infection is cleared, 99% of activated and effector cells die - Wasteful to keep immune response turned on - Left with memory cells to prep immune system under reinfection
36
how is the immune response downregulated?
by Tregs and cytotoxic T cells inhibitory immune checkpoints
37
what are inhibitory immune checkpoints?
Inhibitory immune checkpoints expressed on lymphocytes – when they bind a ligand, it causes inactivation of the lymphocyte
38
what is an example of an inhibitory immune checkpoint?
e.g. CTLA-4 (induced on activated T cells) binds with high avidity to B7. - Engagement of CD28 on naïve T cells with B7 provides the co-stimulatory signal for activation of naïve T cell - Once T cell has been activated, CTLA-4 engagement with B7 inhibits T cell activation and switch it off (higher avidity than CD28-B7
39
give an example of how inhibitory immune checkpoints are involved in terminating the immune response:
lymphocyte receptors with immunoreceptor tyrosine inhibitory motifs (ITIM) – when phosphorylated, these inhibit lymphocytes - FcγRIIb found on B lymphocytes – when it binds IgG it switches the B cell off - PD-1 on activated B and T lymphocytes – interacts with PD-ligand, which is widely expressed - PD = programmed death (downregulation and apoptosis of B cell)
40
how do cancer cells subvert immune checkpoints?
- Cancer cells express PD-ligand which switches off the lymphocytes - Agents that target immune checkpoints may be used in cancer immunotherapy.

Immunology (8 decks)

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