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Clinical Immunology > Lecture 1 - T cells > Flashcards

Lecture 1 - T cells Flashcards

1
Q

Differences between innate and adaptive immunities

A

Innate:

  • non-specific
  • rapid response

Adaptive:

  • specific
  • slow response
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2
Q

Cells in innate immunity

A
  • macrophage
  • dendritic cell
  • mast cell
  • NK cells
  • complement protein
  • granulocytes (eosinophil, basophil, neutrophil)
  • gamma delta T cell
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3
Q

Cells in adaptive immunity

A
  • B cells
  • T cells (CD4+, CD8+)
  • antibodies
  • gamma delta T cells
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4
Q

Types of adaptive immunity

A
  • Humoral

- Cell-mediated

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5
Q

Humoral immunity

A
  • B cells produce the antibodies that mediate this response
  • Main defence against extracellular microbes
  • Antibodies bind to microbes to help eliminate them
  • Antibodies can activate different effector mechanisms
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6
Q

Cell-mediated immunity

A
  • Mediated by T cells and their products (cytokines)

- Main defence against intracellular microbes (viruses and bacteria)

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7
Q

How T cells are made

A
  1. Precursors travel from the bone marrow via blood to the thymic cortex
  2. At the thymic cortex, the precursors acquire TCRs, CD4 and CD8 coreceptors
  3. Positive and negative selection occurs in the thymus. Positive selection promotes survival of cells when their TCRs can bind their own MHC with low affinity
  4. Negative selection eliminates self-reactive thymocytes
  5. In the medulla, thymocytes will differentiate into CD4+ or CD8+ T cells, and mature T cells are released into circulation
  6. Differentiation of these cells into regulatory T cells and gamma delta T cells also occurs
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8
Q

Routes of antigen entry and elimination

A
  • Antigens can enter the body through openings in the skin, respiratory tract or gastrointestinal tract
  • They are captured by dendritic cells and the lymphatic systems transports them to regional lymph nodes
  • Antigens that enter the blood stream are captured by the antigen-presenting cells in the spleen
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9
Q

How naive and effector T cells are activated by antigens

A
  • Naive T cells circulate through lymph nodes
  • They recognise the antigens that dendritic cells have transported to the lymph nodes
  • T cells are activated to differentiate into effector cells
  • These effector cells may remain in the lymphoid organs to help B cells
  • They can also migrate to sites of infection, and at these sites, the effector cells are activated by antigens and perform their various functions (e.g. macrophage activation)
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10
Q

Antigen recognition by innate immune cells

A
  • recognition of molecular structures that are shared by microbes but are not present on mammalian cells
  • happens through PAMPs and PRRs
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11
Q

PAMPs (pathogen-associated molecular patterns) in antigen recognition

A
  • recognise the microbial products that are essential for their survival (ensures that the microbes cannot discard targets of the innate immunity to avoid the host’s immune system)
  • recognition of molecules released from damaged and dying cells (DAMPs/ damage-associated molecular patterns caused by infection and injury to healthy cells)
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12
Q

PRRs (pattern recognition receptors) in antigen recognition

A
  • recognise PAMPs
  • not specific for a particular antigen/pathogen
  • germline encoded
  • expressed by dendritic cells, phagocytes, epithelial cells and other cells that occupy tissues and organs
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13
Q

Cellular localisation of PRRs

A
  • toll-like receptors that are expressed on the cell surface and bind extracellular PAMPs: 1, 2, 4, 5, 6 and lectin receptors
  • toll-like receptors that are expressed on endosomal membranes and recognise nucleic acids of phagocytosed microbes: 3, 7, 8 and 9
  • there are also cytoplasmic sensors (NOD-like receptors and RIG-like receptors)
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14
Q

Antigen capture and presentation by dendritic cells

A
  • immature dendritic cells in the skin (Langerhan cells) or dermis (dermal dendritic cells) capture antigens that enter through the epidermis and transport them to regional lymph nodes
  • during this migration, the dendritic cells mature and become efficient antigen-presenting cells
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15
Q

Role of CD4+ and CD8+ T cells in antigen recognition

A
  • CD4+ T cell = T helper cell
  • CD8+ T cell = Cytotoxic/ NK T cell
  • T helper cells recognise antigens captured by the APC (monocyte or macrophage) and produce cytokines that activate the macrophage to ingest the antigen, and inflammatory responses which also destroy the antigen
  • Cytotoxic T cells are activated by cells that present internal antigens (e.g. virus, tumour, bacteria multiplying in the cell) and they kill the infected cell
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16
Q

Role of cytokines during the innate immune response

A
  • IL-12 – stimulates differentiation of naïve CD4+ T-cells to TH1 subset of effector cells
  • IL-1, IL-6 and IL-23 – stimulates differentiation of naïve CD4+ T-cells to TH17 subset of effector cells
  • IL-15 – promotes survival of memory Cytotoxic T cells
  • IL-6 – promotes production of antibodies by activated B-cells
17
Q

Stimulation of adaptive immunity

A

Antigen recognition by lymphocytes provides signal 1 for the activation of the lymphocytes and molecules induced by innate response to microbes provide signal 2 (eg. costimulator, complement fragment)

18
Q

Other costimulatory pathways

A
  • Activation of T-cells induces the expression of CD40L which interacts with the CD40 on APC 
  • Stimulates the expression of B7 molecules and secretion of cytokines by APC to further amplify T-cell activation
19
Q

Clonal Selection Hypothesis

A
  • Lymphocytes specific for a large number of antigens exist before exposure to an antigen
  • An antigen is specifically recognised by a pre-existing clone of lymphocytes, leading to the proliferation and differentiation of that clone alone – clonal expansion
  • A clone refers to a lymphocyte of one specificity and its progeny
  • Provides specificity – ensures that the adaptive immune response to a microbe is targeted only to that microbe
20
Q

Role of IL-2 in promoting and controlling cell responses

A
  • Resting (naive) T lymphocytes express the IL-2Rβγ complex, which has a moderate affinity for IL-2
  • Activation of the T cells by antigen, costimulators, and IL-2 leads to expression of IL-2Rα chain and the high affinity IL-2Rαβγ complex
  • IL-2 stimulates survival and proliferation of Tcells, = autocrine growth factor
  • IL-2 also maintains regulatory T cells and so controls immune responses (e.g., against self antigens)
21
Q

Differentiation of CD4+ T-cells into effector cells

A
  • Naïve CD4+ T-cells may differentiate into distinct subsets of effector cells in response to antigen, costimulators, and cytokines
22
Q

Development of TH1, TH2, and TH17 subsets

A
  • Cytokines produced early in the innate or adaptive immune response to microbes promote the differentiation of naive CD4+ T cells into TH1, TH2, or TH17 cells by activating transcription factors that stimulate production of the cytokines of each subset (induction)
  • Progressive activation leads to stable changes in the expressed genes (commitment)
  • Cytokines promote the development of each population and suppress the development of the other subsets (amplification)
  • These principles apply to all three major subsets of CD4+ effector T cells
23
Q

IL-12 stimulating a TH1 response

A
  • IL-12 is produced by dendritic cells and macrophages in response to microbes, including intracellular microbes
  • IFNγ produced by NK cells (all part of the early innate immune response to the microbes)
  • IL-12 & IFN activate T-bet, STAT1 and STAT4&raquo_space; the differentiation of naive CD4+ T cells to the TH1 subset
  • IFNγ produced by the TH1 cells amplifies this response and inhibits TH2 and TH17 responses
24
Q

Effector mechanisms – CD4+ T-cells (TH1)

A

TH1 cells secrete IFN-γ, which acts on:

  • macrophages to increase phagocytosis and killing of microbes in phagolysosomes
  • B cells to stimulate production of IgG antibodies that opsonize microbes for phagocytosis

The cells also produce TNF, which activates neutrophils and promotes inflammation

25
Q

IL-4 stimulating TH2 differentiation

A
  •  IL-4 is produced by activated T cells or by mast cells and eosinophils (especially in response to helminths)
  •  IL-4 activates the transcription factors GATA-3 and STAT6, which stimulate differentiation of naive CD4+ T cells to become TH2 cells
  •  IL-4 produced by these TH2 cells amplifies the Th2 response and inhibits the development of TH1 and TH17 cells
26
Q

Effector mechanisms – CD4+ T-cells (TH2)

A
  •  IL-4 (& IL-13) act on B cells to stimulate production of IgE
  •  IL-4 is an autocrine growth & differentiation cytokine for TH2 cells
  •  IL-5 activates eosinophils - important for defence against helminthic infections
  •  IL-4 & IL-13 induce alternative (M2) macrophage activation, and inhibit classical (M1) macrophage activation
27
Q

Macrophage activation

A
  •  M1 macrophages are induced by microbial products and IFNγ. They are microbicidal, but may create harmful inflammation
  •  M2 macrophages are induced by IL-4 and IL-13. They drive tissue repair and fibrosis
28
Q

Development of TH17 cells

A
  •  IL-1 and IL-6 (from APC) and TGF-β (from macrophage and other cells) activate the transcription factors RORγt and STAT3, which stimulate the differentiation of naive CD4+ T cells to the TH17 subset
  •  IL-23 is also produced by APC, (especially in response to fungi) & stabilizes TH17 cells
  •  TGF-β may promote TH17 responses indirectly by suppressing TH1 and TH2 cells, both of which inhibit TH17 differentiation
  •  IL-21 produced by TH17 cells amplifies this response
29
Q

Effector mechanisms – CD4+ T-cells (TH17)

A

Cytokines produced by Th17 cells stimulate local production of chemokines that recruit neutrophils and other leukocytes, increase production of antimicrobial peptides (defensins), and promote epithelial barrier functions

30
Q

Regulatory cells

A
  •  Regulatory T cells are generated by self antigen recognition in the thymus (“natural regulatory T-cells”) and by antigen recognition in peripheral lymphoid organs (“inducible regulatory T-cells”)
  •  The development and survival of regulatory T cells require IL-2 and the transcription factor FoxP3
  •  In peripheral tissues, regulatory T cells suppress the activation and effector functions of self-reactive and potentially pathogenic lymphocytes
31
Q

Effector mechanisms – CD8+ T-cells

A

CTLs kill target cells by two main mechanisms:

  1. Complexes of perforin and granzymes are released from the CTL by granule exocytosis and enter target cells. The granzymes are delivered into the cytoplasm of the target cells by a perforin-dependent mechanism, and they induce apoptosis
  2. FasL is expressed on activated CTLs, engages Fas on the surface of target cells, and induces apoptosis
32
Q

Specificity

A

- Different antigens results in the generation of effector T-cells specific for that antigen

33
Q

Memory

A
  •  Responses to subsequent exposures are more rapid, larger and qualitatively different 
  • Occurs because exposure generates long-lived memory cells that are more efficient at responding and eliminating the antigen
34
Q

Contraction

A
  •  Normal responses wane with time after antigen stimulation, returning the immune system to its resting basal state (‘homeostasis’)
  •  Occurs because elimination of antigen stimulation eliminates the stimulus required for lymphocyte survival and activation
35
Q

Diversity

A

Enables immune system to respond to a large variety of antigens

36
Q

Specialisation

A

Generates responses that are optimal for defense against different types of microbes

37
Q

Clonal expansion

A

Increases number of antigen-specific lymphocytes to keep pace with microbes

38
Q

Nonreactivity to self

A

Prevents injury to host during responses against foreign antigens

Clinical Immunology (15 decks)

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