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Immunolgy > Differentiation/function of CD4+ & CD8+ Effector T cells > Flashcards

Differentiation/function of CD4+ & CD8+ Effector T cells Flashcards

1
Q

what are the functions of CD4+ effector T cells?

A
  • > recruit and activate phagocytes(macrophages/neutrophils) and other leukocytes that destroy intracellular and some extracellular microbes
  • > help B lymphocytes produce antibodies
  • > some can activate eosinophils to destroy particular types of microbes
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2
Q

what is cell-mediated immunity

A

the type of host defence that is mediated by T lymphocytes, and it serves as a defence mechanism against intracellular and phagocytosed microbes (cell-associated microbes)

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3
Q

how do CD4+ effector T cells activate phagocytes

A

via surface molecules, principally CD40 ligand and secreted cytokines

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4
Q

how are CD4+ T cells generated

A

by antigen recognition in secondary lymphoid organs
->but most of them leave these organs and migrate to peripheral sites of infection where they function in microbe elimination

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5
Q

what is delayed type hypersensitivity

A

T cell dependent injurious reaction where normal tissues are damaged from inflammation (leukocyte recruitment/activation) that accompanies many of the reactions of CD4+ T lymphocytes
-> TH1-mediated reaction that can cause significant tissue injury

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6
Q

what does the term hypersensitivity mean

A

tissue damage due to an immune response

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7
Q

how are the subsets of CD4+ effector T cells distinguished

A

by the type of cytokines they produce, the transcription factors they express and epigenetic changes in specific cytokine gene loci
->involved in host defence against different microbes

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8
Q

what are the signature cytokines produced by TH1, TH2 and TH17 CD4+ effector T cells

A

TH1 cells: IFN-Y
TH2 cells: IL-4, IL-5 and IL-13
TH17 cells: IL-17 and IL-22

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9
Q

what determines the the effector functions of T cells and their role in diseases?

A

the cytokines that they produce

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10
Q

what are some of the chemokine receptors that TH1, TH2 and TH17 CD4+ effector T cells express and what do they bind to?

A

TH1 cells: CSCR3, CCR5 (bind to chemokines elaborated in tissues during innate immune responsess), also express high levels of ligands for p and e selectin
TH2 cells: CCR3, CCR4, CCR8 (recognize chemokines that are highly expressed at sites of helminthic infection of allergic reactions)
TH17 cells: CCR6 (bind to chemokine CCL20)

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11
Q

what two things are required for the differentiation of CD4+ subsets??

A

involves transcriptional activation and epigenetic modification of cytokine genes

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12
Q

describe the three stages involved in the process of CD4+ T cell differentiation
*******

A
  1. induction: cytokines act on T cells stimulated by antigen and costimulators to induce the transcription of cytokine genes that are characteristic of each subset
  2. commitment: the subset’s cytokine genes become fixed in a transcriptionally active state (genes that encode cytokines not produced by that subset remain inactive) and the differentiating T cell becomes progressively committed to one specific pathway
  3. amplification: cytokines produced by any given subset promote the development of this subset and inhibit differentiation toward other CD4+ subpopulations. the net result is the accumulation of cells of one subset
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13
Q

what cells produce the cytokines that derive the development of CD4+ T cell subsets

A

produced by APCs (primarily dendritic cells and macrophages) and other immune cells present in the lymphoid organ where the immune response is initiated

  • > DCs are activated to produce cytokines when they encounter microbes and may produce different cytokines depending on the microbe, influencing T cell subset development
  • > DCs may selectively promote either TH1 or TH2 differentiation (without cytokine input)
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14
Q

how are the distinct cytokine profiles of differentiated cell populations controlled?

A
  1. by particular transcription factors that activate cytokine gene expression
  2. by chromatin modifications affecting accessibility to the promotors and regulatory elements of cytokine genes that these transcription factors bind to
    (these epigenetic changes ensure that each subset can produce only its characteristic collection of cytokines
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15
Q

what particular leukocytes are recruited by the types of CD4+ effector T cells

A

T 1 activate macrophages
T 17 recruit mostly neutrophils but some macrophages
T 2 activate eosinophils

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16
Q

how derives the differentiation of TH1 cells

A

mainly the cytokines IL-12 and IFN-Y

  • > occurs in response to microbes that activate DCs, macrophages and NK cells
  • > stimulated by many intracellular bacteria and some parasites as well as viruses and administered protein antigens (all of which elicit innate immune reactions which produce cytokines that promote TH1 development)
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17
Q

what transcription factors do IFN-Y(produced by NK cells) and IL-12(produced by DCs/macrophages) activate to stimulate TH1 differentiation

A

T-bet, STAT1 and STAT4
IFN-Y activates STAT1 and T-bet which promotes IFN-Y production which sets up a positive amplification loop which derive TH1 differentiation
-> IL-12 binds to receptors and activates STAT1

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18
Q

what is the principle function of TH1 cells

A

To activate macrophages to ingest and destroy microbes

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19
Q

what is the principle macrophage-activating cytokine and what ligand does it work with to activate macrophages

A

IFN-Y acts with ligand CD40

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20
Q

what is classical macrophage activation

A

macrophage activation resulting in increased microbicidal activity (enhance macrophage killing)

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21
Q

why would TH1 produce IL-10

A

serves as a neg feedback loop to suppress TH1 activation by inhibiting DCs and macrophages

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22
Q

how do activated macrophages kill phagocytosed microbes

A

mainly by actions of ROS, nitric oxide and lysosomal enzymes which are all produced within lysosomes which fuse with the phagosomes

23
Q

what are the 3 main responses of activated macrophages by TH1 cells? what are the roles of these responses?`

A
  1. production of ROS, NO, increased lysosomal enzymes
    (killing of microbes in phagolysosomes)
  2. secretion of cytokines (TNF, IL-1, IL-12) and chemokines:
    (TNF, IL-1, chemokines = leukocyte recruitment)
    (IL-12 = TH1 differentiation, IFN-y production)
  3. increased expression of B7 costimulators, MHC molecules:
    (increases T cell activation)
24
Q

x-linked hyper-IgM syndrom

A

inherited mutations in CD40L genes

25
Q

what is TH2 differentiation stimulated by?

A

by the cytokine IL-4 and occurs in response to helminths and allergens which cause chronic T cell stimulation

26
Q

if the TH2 depends of IL-4 but IL-4 is produced by TH2 cells, where does the IL-4 come from before TH2 cells develop?

A
  • may be produced by mast cells and possibly innate lymphoid cells
  • antigen-stimulated CD4+ T cells may secrete small amounts from their initial activation
27
Q

what transcription factor does IL-4 activate to stimulate TH2 development?

A

STAT6

28
Q

what transcription factor does STAT6 induce the expression of and what does it do?

A

GATA-3 enhances the expression of the TH2 cytokine genes IL-4, IL-5 and IL-13 and ultimately commits differentiating cells towards the TH2 phenotype

29
Q

what is the function of TH2 cells?

A

Stimulate IgE-, mast cell- and eosinophil-mediated reactions that serve to eradicate helminthic infections

30
Q

what are some of the important actions of IL-4 (the signature cytokine of the TH2 subset)

A
  1. stimulates B cell Ig heavy chain class switching to the IgE isotype (IgE antibodies play a role in eosinophil -mediated defence against helminthic infections)
  2. stimulates the development of TH2 effector cells from naive CD4+ T cells
  3. together with IL-13, contributes to an alternative form of macrophage activation distinct from the macrophage response to IFN-Y
  4. IL-4 (and IL-13) stimulate peristalsis in the gastrointestinal tract
  5. IL-4 (and IL-13) stimulate recruitment of leukocytes
31
Q

what are some of the important actions of IL-13

A

structurally and functionally similar to IL-4 and also plays a key role in defence against helminths and in allergenic disease

  • contributes to an alternative form of macrophage activation
  • stimulate recruitment of leukocytes
  • stimulates mucous production in airway epithelial cells
32
Q

what are some of the important actions of IL-5

A

activator of mature eosinophils(and stimulates the growth/differentiation of them) and serves as the principle link between T cell activation and eosinophilic inflammation
-activated eosinophils are able to kill helminths

33
Q

describe IgE and eosinophil-mediated reactions

A

IL-4 (and IL-13), secreted by TH2 or by TFH cells, stimulates the production of helminth-specific IgE antibodies, which opsonize the helminth and promote binding of eosinophils ( activated by IL-5) which can then destroy the helminths

34
Q

why is the activation of mast cells important for the role of TH2 cells in host defence

A

bc they secrete cytokines such as TNF and chemokines and lipid mediators, all of which induce local inflammation that helps to destroy the parasites

35
Q

what is barrier immunity

A

host defence at the barriers with the external environment

-TH2 cells play an important role

36
Q

what is alternative macrophage activation

A
  • the macrophage response to TH2 cytokines

- initiates repair after diverse types of tissue injury, induces scaring and fibrosis (anti-inflammatory effects)

37
Q

the TH17 subset is primarily involved in

A

combatting microbes by recruiting leukocytes(mainly neutrophils) to sites of infection and inducing inflammation (critical for destroying extracellular bacteria and fungi and contributes to inflammatory diseases
-combatting intestinal infections /intestinal inflammation

38
Q

what is the development of TH17 cells stimulated by?

A

pro-inflammatory cytokines produced in response to bacteria and fungi

39
Q

what cytokines promote CD4+ differentiation to TH17

A

IL-6, IL-1 and IL-23 (bacteria/fungi act on DCs to stimulate the production of these cytokines)

40
Q

what transcription factors is TH17 development dependent on and what cytokines induce the production of these transcription factors

A

RORyt: production induced by TGF-B and mainly IL-6 and IL-1
and
STAT3: production induced mainly by IL-6

41
Q

IL-17 functions to

A
  1. stimulate the production of chemokines and other cytokines (such as TNF) that recruit neutrophils to ingest and destroy bacteria and fungi
  2. stimulates the production of antimicrobial substances
42
Q

role of CD8+ cytotoxic T lymphocytes

A

kill cells that have viruses in the cytosol by killing the infected cell and eradicate many tumours
-capable of secreting cytokines, mostly IFN-y, that function to activate phagocytes (contribute to classical macrophage activation)

43
Q

how may CD4+ helper T cells promote CD8+ T cell activation?

A
  1. May secrete cytokines that stimulate the differentiation of CD8+ T cells
  2. Activated helper T cells express CD40 ligand which may bind to CD40 on antigen loaded DCs. This activates the APCs to make them more efficient at stimulating the differentiation of CD8+ T cells (in part by inducing expression of co-stimulators)
44
Q

what cytokines contribute to the differentiation of CD8+ T cells and the maintenance of effector and memory cells of this lineage

A
  1. IL-2: promotes proliferation/differentiation into CTLs and memory cells
  2. IL-12 & type 1 IFNs: stimulate differentiation into effector CTLs
  3. IL-15: important for the survival of memory CD8+ cells
  4. IL-21: plays role in induction of CD8+ T cell memory and the prevention of CD8+ T cell exhaustion
45
Q

what is T cell exhaustion

A

the responses of CD8+ T cells in some chronic viral infections may be initiated but gradually extinguished

  • have reduced production of IFN-y and increased expression of multiple inhibitory receptors such as PD-1
  • reduced proliferation
46
Q

how CD8+ CTLs kill target cells

A

involves specific recognition of target cells and delivery of proteins that induce ell death
-target cells that express the same class 1 MHC-antigen that triggered the proliferation of naive CD8+ T cells from which they are derived
-granule cytotoxic proteins that do the killing are secreted into the synapse and diffuse to the infected cell (delivery of the lethal hit) and kills the cell
-Cytokines and costimulators are unnecessary for CTL
mediated killing

47
Q

how do CTL bind and react to the target cell

A

by using its antigen receptor, coreceptor (CD8) and adhesion molecules( ICAM-1, the principal ligand for the LFA-1 integrin)

48
Q

what are the major cytotoxic proteins in the granules of CTLs (and NK cells)

A

granzymes and perforin(facilitates delivery of the granzymes into the cytosol of the target cell)
-Perforin either causes membrane holes or endocytosis of granzymes by target cell

49
Q

what is serglycin

A

proteoglycan which serves to assemble a complex containing granzymes and perforin

50
Q

Fas ligand (FasL) role

A

are membrane proteins expressed on CTLs once activated and bind to the death receptor Fas (expressed on many cell types)
-This interaction results in apoptosis of Fas-expressing targets

51
Q

what cytokine does CD8+ T cells produce

A

the macrophage-activating cytokine IFN-y

52
Q

how do CD8+ T cells develop in a similar manner to CD4+ T cells

A

antigen recognition, costimulation, clonal expansion, differentiation, migration to inflammatory site where only recognition of only MHC I cells occurs (means that they do not harm normal (uninfected)host tissue)

53
Q

Two types of situations where cell can’t kill intracellular microbes

A
  1. Some viruses live and replicate in cells that are incapable of destroying microbes (Hepatitis in liver cells)
  2. Some microbes can escape phagocytic
    vacuoles and live in the cytoplasm

Immunolgy (8 decks)

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