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PM3 - Infection and immunity > T cells - adaptive immunity > Flashcards

T cells - adaptive immunity Flashcards

1
Q

Hallmarks of adaptive immunity

A

specifity and diversity
specilisation
non-reactivity to self
clonal expansion
contraction and homeostasis
memory

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2
Q

humoral adaptive immunity
components and function

A

antibodies produced by B cells
neutralization
phagocytosis
opsonization
complement activation

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3
Q

innate immune system and adptive immune system
interplay

A

innate IS provides signals to stimulate proliferation and differentiation of adaptive cells to antigen-specific T and B cells

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4
Q

Adaptive cell development

A

LT-HSC
ST-HSC -> CLP, CMP, MEP
CLP -> T or B cell lineage
T cell commitment dirven by Notch1 and GATA3
B cell commitment by Pax5

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5
Q

driver of proliferation of commited progenitor cells

A

develop from common lymphoid progenitor
proliferate in response to cytokines
later through signals generated by pre-Ag receptor -> selection of cells with successfully rearranged set of receptor genes

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6
Q

T cell development until committment

A

from HSC and CLP development of TSC (thymic seeding cell) -> migration from bone marrow to thymus
ETP = DN1 (early thymic progenitor, double negative 1)
DN1: CD44+, develpment to DCs, NK cells, macrophages or DN2a
DN1-checkpoint: commitment when transitioning to DN2a, Notch inhibits alternative fate, start of RAG expression

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7
Q

T cell development of committed progenitors

A

commitment in DN1 to DN2a transition (DN1 checkpoint -> RAG expression start)
DN2 = CD44+ and CD25+
DN2b -> start of beta-chain rearrangement of TCR

DN3a -> continuing beta rearrangement
DN3 = CD25+ (CD44-)

beta selection Checkpoint: for transition form DN3a to DN3b, marks committment to alpha/beta lineage

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8
Q

T cell development of alpha/beta commited cells

A

alpha/beta committment in passing beta selection checkpoint from DN3a to DN3b (CD25+)
to DN4 (CD44- CD25-)
to DP cells (double positive CD4+ and CD8+) -> alpha chain rearrangement

POSITIVE & NEGATIVE SELECTION CHECKPOINT: establish central tolerance
positive selection in DP cells: cTEC expressing MHC-peptide, DP receive critical survival signals when binding with low-avidity
transition to SP cells (commit to CD4 or CD8)
negative selection in SP cells: mTEC express TRA on MHC (plus TRA transfer to DC) -> recognition leads to deletion

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9
Q

positive selection checkpoint T cells

A

POSITIVE & NEGATIVE SELECTION CHECKPOINT: establish central tolerance
positive selection in DP cells: cTEC expressing MHC-peptide, DP receive critical survival signals when binding with low-avidity
then transition to SP cells (commit to CD4 or CD8)

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10
Q

negative selection checkpoint T cells

A

POSITIVE & NEGATIVE SELECTION CHECKPOINT: establish central tolerance
positive selection in DP cells and cTEC
then transition to SP cells (commit to CD4 or CD8)
negative selection in SP cells: mTEC express TRA on MHC (plus TRA transfer to DC) -> recognition leads to deletion

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11
Q

checkpoint 3 in T cell development

A

POSITIVE & NEGATIVE SELECTION CHECKPOINT: establish central tolerance
positive selection in DP cells: cTEC expressing MHC-peptide, DP receive critical survival signals when binding with low-avidity
transition to SP cells (commit to CD4 or CD8)
negative selection in SP cells: mTEC express TRA on MHC (plus TRA transfer to DC) -> recognition leads to deletion

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12
Q

DN1 surface markers

A

CD44+ CD25-
=ETP
can develop to NK, DC, macrophages or DN2a
DN1 checkpoint: Transition to DN2a, committment to T cell lineage (notch prevents reversion), induction of RAG proteins

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13
Q

DN1 checkpoint

A

first checkpoint
marks committment to T cell lineage (notch prevents reversion)
transition from DN1 to DN2a
induction of RAG proteins

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14
Q

first checkpoint T cell development

A

DN1 checkpoint
marks committment to T cell lineage (notch prevents reversion)
transition from DN1 to DN2a
induction of RAG proteins

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15
Q

second T cell checkpoint

A

beta-selection checkpoint
for transition form DN3a to DN3b, marks committment to alpha/beta lineage

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16
Q

beta selection checkpoint

A

second T cell checkpoint
for transition form DN3a to DN3b, marks committment to alpha/beta lineage

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17
Q

TCR rearranegment
TCR composition, what creates variance

A

alpha and beta chain with VR and CR
beta chains VR has V, D and J segements, alphas only V and J

non-homologous rearrangement of TCR
- somatic recombination (V(D)J)
- addition/deletion of N and P nucleotides
- transcriptional and RNA processing

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18
Q

non homolougos rearranegment of TCR via

A

non-homologous rearrangement of TCR
- somatic recombination (V(D)J)
- addition/deletion of N and P nucleotides
- transcriptional and RNA processing

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19
Q

DN3 surface markers

A

CD44- CD25+

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20
Q

DN2 surface markers

A

CD44+ CD25+

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21
Q

DN4 surface markers

A

CD44- CD25-

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22
Q

MHC complexes

A

for Ag binding -> presentation
peptides need to be bound to MHC -> MHC RESTRICTION of T cells (or MHC like receptors)
MHCI: on all nucleated cells, presents endogenous Ag to CD8
MHCII: on professional APC (macrophages, B cells and DC), present exogenous Ag to CD4

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23
Q

TCR complex

A

TCR: alpha and beta heterodimer
CD3: epsilon + delta or gamma heterodimer, covalent linkage to TCR, 1 ITAM
zeta chains: homodimer, 3 ITAM
CD4/CD8: interact with MHC, required for signalling and strengthen TCR-MHC binding

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24
Q

TCR signalling

A

TCR and co-receptors cluster in lipid rafts
Ag recognition
phosphorylation of ITAM by Lck
recruitment of Zap-70
over LAt and Grb2 acttivation of PLCg and RAS/MAPK pathway

activation of distant signalling enzymes and TFs -> alterations in gene expression

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25
Q

Lck

A

kinase phosphorylating ITAMs upon TCR signalling
causes recruitment of Zap-70 (LAT - Gr2b - PLC and ras/mapk)

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26
Q

signals required for T cell activation

A

TCR-MHC -> activation
CD28-B7 (CD80/CD86) -> survival
cytokines -> differentiation

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27
Q

co-receptors

A

prevent or eable TCR signalling
CD28 and B7 -> required for T cell maturation
CTLA4 -> inhibition via competition for B7
PD1 -> inhibition via recruitment of phosphotases (ITIMs)

Superantigens: directly bind MHC and TCR, antigen-specifity is not necessary

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28
Q

inhibition mechanism CTLA4

A

competitive inhibition (B7 binding)

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29
Q

inhibition mechanism PD-1

A

recruitment of phosphatases (ITIM)

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30
Q

CD62

A

selectin
P, E and L

CD62P on ECs activated by histamin or thrombin -> binds neutrophils, monocytes or T cells
CD62E on EC sactivated by cytokines -> binds neutrophils, monocytes or T cells
CD62L on immune cells -> binds ECs adhesion molecules

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31
Q

CD62L

A

selectin
on immune cells -> binds adhesion molecules on ECs

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32
Q

CD62P

A

selectin
on ECs activated by histamins orthrombin -> recognizes neutrophils, monocytes or T cells

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33
Q

CD62E

A

selectin
on ECs activated by cytokines -> recognizes neutrophils, monocytes or T cells

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34
Q

integrins

A

CD11 and CD18
LFA-1: (CD11a) on immune cells bining ICAM1/2 on ECs
Mac-1: (CD11b) on neutrophils, monocytes and DCs binding ICAM1/2 on ECs

CD49 and CD29
VLA-4: (CD49a) on monocytes, naive and effector T cells binding VACM-1 on ECs
a4b7: (CD49b) on immune cells (esp GIT) binding VCAM1 + MadCAM1 on ECs in gut

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35
Q

CD11aCD18

A

integrin
LFA-1
on immune cells binding ICAM 1/2 on ECs

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36
Q

CD11bCD18

A

integrin
Mac-1
on monocytes, neutophils and DC binding ICAm 1/2 on ECs

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37
Q

LAF-1

A

integrin
CD11aCD18
on immune cells binding ICAm 1/2 on ECs

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38
Q

Mac-1

A

integrin
CD11bCD18
on monocytes, neutrophils and DC binding ICAm 1/2 on ECs

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39
Q

CD49aCD29

A

integrin
VLA-4
on monocytes, naive and effector T cells
binding VCAM-1 on ECs

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40
Q

CD49bCD29

A

integrin
a4b7
on immune cells, especially gut
binding VCAM-1 and MadCAM-1 on ECs in GIT

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41
Q

VLA-4

A

integrin
CD49aCD29b
on monocytes, naive and effector T cells
binding VCAM-1 on ECs

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42
Q

a4b7

A

integrin
CD49bCD29
on immune cells, especially gut
binding VCAM-1 and MadCAM-1 on ECs in GIT

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43
Q

leukocyte extravasation process

A

ECs activation leads to upregulation of adhesion molecules
selectin mediate initial low-affinity adhesion and initiate leukocyte rolling
chemokine-mediates increase of intgrin affinity
stabel intergin-mediated adhesion to ECs
transmigration

44
Q

life cycle naive T cells

A

residing in LN and screening of fluids
proliferation post-thymically while maintaining naive phenotype
establishment of homeostatic proliferation
recognition of self-Ag and IL-7 required for survival

stable population of quinescent naive T cells essential for adaptive immunity
regulated via p27kip, KLF2 and Schlafen

45
Q

survival signals for naive T cell population

A

IL7

or (and?) quinescence mediated by p27kip, KLF2 and Schlafen

46
Q

Surface molecule expression change in effector T cells

A

activation of naive T cells induces transition to lymphoblasts and then effector lymphocytes
differentiation in subsets

surface molecule expression changes with time -> activating molecules to inhibitory molecules
CD62L for lymph node homing
CD25 (IL2R)
CD40L
CTLA4

47
Q

IL2

A

T cell GF secreted by mature DCs
promotes growth, survival and differentiation
maintenance and functionality of Tregs, proliferation and differentiation of effector and memory T cells

naive T cells express low-affinity IL2Rbg complex
IL2 by DC during activation leads to expression of alpha chain
IL2abg complex has high-affinity
leads to IL-2 induced T cel expansion and endogenous IL2 expression

48
Q

CD25

A

IL2-R
naive T cells express low-affinity IL2Rbg complex
IL2 by DC during activation leads to expression of alpha chain
IL2abg complex has high-affinity
leads to IL-2 induced T cel expansion and endogenous IL2 expression

IL2 = T cell GF secreted by mature DCs
promotes growth, survival and differentiation

49
Q

IL2-R

A

CD25
naive T cells express low-affinity IL2Rbg complex
IL2 by DC during activation leads to expression of alpha chain
IL2abg complex has high-affinity
leads to IL-2 induced T cel expansion and endogenous IL2 expression

IL2 = T cell GF secreted by mature DCs
promotes growth, survival and differentiation

50
Q

Memory T cells

A

central, effector or tissue-resident
persist in absence of pathogen
can have effector functions
can be autoreactive, abberrantly activated or malignant and contribute to numerous inflammatory syndromes

maintenance dependent on cytokines constitutively supporting low-level proliferation -> IL7, STAT5

51
Q

IL7

A

survival of naive T cell population
maintenance and promoting of consttutive low-level proliferation of memory T cells

52
Q

central memory T cells

A

persist in absence of pathogen
can be autoreactive, abberrantly activated or malignant and contribute to numerous inflammatory syndromes

lymph node homing
expression of CCR7 and CD62L
upon activation main function is RAPID PROLIFERATION -> they differentiate into effector cells

maintenance dependent on cytokines constitutively supporting low-level proliferation -> IL7, STAT5

53
Q

effector memory T cells

A

persist in absence of pathogen
have effector functions
can be autoreactive, abberrantly activated or malignant and contribute to numerous inflammatory syndromes

no or only low expression of CD62L and CCR7 (not lymph node homing)
upon activation their mein function is RAPID EFFECTOR RESPONSE

maintenance dependent on cytokines constitutively supporting low-level proliferation -> IL7, STAT5

54
Q

deletion of T cells
+ mechanism

A

apoptosis is essential for termination of immune response
apoptosis mitochondrial or death-receptor mediated (FasL)

e.g. TCR signalling w/o co-stimulus may activate Bim -> mt cytochrome c

55
Q

aging of immune system

A

contributes to increased moridity and mortality of elderly

expansion of effector memory T cell subset (CD4+ CD28-) that ca e autoreactive and non-specific main characteristic of immuno senescence

56
Q

termination of immune response

A

over time uregulation of inhibitory co-receptors (CTLA4)
deletion of effector T cells via apoptosis essential (mitochondrial or death receptor)
small percentage become memory T cells

57
Q

function of CD4 helper T cells

A

activation of innate IS
activation of adaptive IS
cell-mediated immunity
licensing DC for cross-priming
influence on CD8 T cells

58
Q

CD4 activating innate IS

A

activate macrophages
licensing of APCs (CD40 interaction leads to upregulation of B7)
induction of monocyte differentiation (macrophages)

59
Q

CD4 activating adaptive IS

A

activation of B cells, CD8 T cells
killing function themselves

60
Q

licensing DCs

A

DC activation via TLR signalling and Ag acquisition
DC interact with CD4 T cells to license DC via CD40 (DC) and CD40L (T) interaction
DC is no primed to cross-present + upregulation of co-stim and down-reg of co-inhib molecules -> allows CD8 activation

61
Q

CD4 influencing CD8 T cells

A

generation of CD8 memory T cells without CD4 immpossible (activation also w/o CD4 possible)
produce cytokines stimulating CTL differentiation
enhance APCs (licensing) to stimulate CTL differentiation

62
Q

differentiation of CD4 cells

A

subsets are induce depending on cytokine milieu
initially reversible but with time epigenetic modifications cause committment
but during co-infections changes have been eobserved

psoitive feedback loops of cytokine production drive differentiation into the on subset

63
Q

TH1 cells

A

Inductor: IL-12 and TNF-a, produced by DCs, macrophages and NK cells
Products: T-bet, IFNg, TNF
Function: antiviral, immunity against extra- and aintracellular bacteria
essential for PHAGOCYTE-MEDIATED HOST DEFENCE
Properties: CCR3 upregulated for migration, CCL3 & 4 secretion for additional recruitment of myeloid cells

loss of Th1 leads to increased Th2 development -> increased IL10 and IL4 -> inhibits microcidal function of macrophages -> increased mortality in infections

64
Q

Inductor of TH1

A

IL-12 and TNF-a, produced by DCs, macrophages and NK cells

65
Q

Product TH1

A

Products: T-bet, IFNg, TNF

66
Q

Function TH1

A

Function: antiviral, immunity against extra- and aintracellular bacteria
essential for PHAGOCYTE-MEDIATED HOST DEFENCE

67
Q

Properties TH1

A

Properties: CCR3 upregulated for migration, CCL3 & 4 secretion for additional recruitment of myeloid cells

68
Q

Consequence of loss of TH1

A

leads to increased Th2 development -> increased IL10 and IL4 -> inhibits microcidal function of macrophages -> increased mortality in infections

69
Q

IL12

A

driver of TH1 differentiation
primary mediator of early innate immunity
primarily produced by DCs and macrophages
stimulates IFNg production in T and NK cells

70
Q

IFNg

A

type II IFN
activation of macrophages and induction of pagocytosis
promotes TH1 differentiation, inhibits TH2
product of TH1

promotes class switching in B cells
upregulation of MHC I and II
upregulation of co-stimulators on APCs
EC activation

71
Q

TH2 cells

A

Inductor: IL4
Products: GATA3, STAT6, IL4, IL13
Function: immunity to extracelular parasites and stimulation of IgE, mast cells and eosinophils to eradicate helminths

increases macrophage numbers via IL4 to fight helminths
M1 polarization

when inflammatory stimulus is eliminated dormins and TH2 cytokines converse response to wound healing

72
Q

Inductor TH2

A

IL4

73
Q

Product TH2

A

GATA3, STAT6
IL4 and IL13

74
Q

Function TH2

A

immunity to extracellular parasites
stimulation of IgE mast cells and eosinophils to eradicate helminths
increase macrophage numbers and drive M1 polarization

when inflammatory stimulus is eliminated they drive the conversion of the response to wound healing

75
Q

GATA3

A

TF iniiated by IL4 and produced by TH2
master regulator of TH2 differntiation
increases IL4, IL5 and IL13 -> positive feedback loop
inhibits IL12R signalling chain -> prevents TH1 differentiation

76
Q

IL4

A

inducer of TH2 diffrentiatin
prdued by activated mast cells, NK and NKT cells, basophils, TH2 and naive T cells
signals via JAk/STAT
promotes TH2 as autokrine GF
stimulates B cell HC class switch to IgE (prmotor of switch region is cytokine regulated!)

77
Q

TH17 cells

A

Inductor: TGFb, IL6, IL23
Products: RORgt, IL17
Function: fight bacteria, fungi and toxoplasmosen, cooperation with TH1 in phagoyte-mediated eliminitation, contrbte to autoimmunity

78
Q

inductor TH17

A

TGFb, IL6 and IL23

79
Q

product TH17

A

RORgt, IL17

80
Q

Function TH17

A

fight bacteria, fungi and toxoplasmosen, cooperation with TH1 in phagoyte-mediated eliminitation, contrbte to autoimmunity

81
Q

RORgt

A

TF
production induced by inflammatory cytokines (e.g. IL1 and IL6)
produced by TH17
drives TH17 response with STAT3

82
Q

STAT3

A

TF
activated by inflammatory cytokines (especially IL-6)
drives TH17 repsonse with RORgt

83
Q

TGFb

A

inducer of TH17 differentiation ( in combination with IL6, IL23) and Treg differentiaion
inhibits TH1 and TH2 differentiation
produced by DC (essential for active levels), also Treg, TAM2, MDSC and tumor cells
MAJOR immunosuppressive towards CD4, CD8, NK cells
increases Tregs and TAMs

TGFb and IL6 -> IL17 (TH17 differentiation)
TGFb -> FoxP3 (Treg, inhibited by IL6!)

84
Q

IL6

A

pro-inflammatory cytokine, induces actute phase response with IL1 and TNFa
produced by DCs, monocytes, macrphages, mast cells, B cells and T cell subsets, tumor cells, fibroblasts ECs, keratinocytes
involved in TH17 differentiation (with TGFb)
production induced by IL1, TNF, PDGF, IL3, GM-CSF, IL17 -> dependent on cell

IL6 is required for constitutive IL17 expression
loss of IL6 -> increase in FoxP3 expressing Tregs

promotes survival, prooliferation, T cell recruitment and subset commitment

85
Q

IL23

A

promotes IL17 production
IL23R not expressed on naive T cells -> not involved in initial TH17 differentiation but required for full and sustained differentiation
stabalized IL17 response
induces IL17, IL1, TNF and IL6 -> inflammation
(IL23R mutation -> protction agianst Chrons)

86
Q

TFH cells

A

follicular helper cells
Inducer: IL21, IL6
Product: Bcl6, IL21
Function: high CXCR5 expression allows migraion along CXCL13 to lymphoid follicles, critical for GERMLINE CENTER FORMATION

TFH markers; CXCR5, ICOS, PD-1, IL21 and BCl-6 -> all essential for GC development

87
Q

Inducer TFH

A

IL21, IL6

88
Q

Product TFH

A

Bcl6, IL21

89
Q

Function TFH

A

high CXCR5 expression allows migraion along CXCL13 to lymphoid follicles, critical for GERMLINE CENTER FORMATION

90
Q

Markers TFH

A

CXCR5, ICOS, PD-1, IL21 and BCl-6 -> all essential for GC development

91
Q

MAIT cells

A

non-conventional T cells
mucosal associated invariant T cells

detect their Ag (5-A-RU) on MR1 (MHC related 1) on APCs
cytotoxic and secrete IFNg

92
Q

MR1

A

MHC-related 1
present Ag -> recognized by MAIT cells (cytotoxic and secrete IFNg)

93
Q

gd T cells

A

on epithelial surfaces
bind phospholigands
cytotoxic and secrete IFNg

94
Q

CD1-restricted ab T cells

A

recognize glycolipids only when presented on CD1 by DCs
cytotoxic and secrete IFNg

95
Q

CD1

A

on DC
can present Ag (glycolipids)
recognize by CD1-restricted ab T cells (cytotoxic and secrete IFNg)

96
Q

Treg cells

A

Inductor: TGFb
Products: FoxP3, TGFb
Function: fine tuning of tolerance by mediating PERIPHERAL TOLERANCE (together with anergy induction)

Loss leads to death via multi-organ immunity

central T regs formed in lymphoid organs
peripheral iTregs induced via TGFb (15% of all Tregs, most common in GIT)

97
Q

function of CD8 T cells

A

PATHOGEN CLEARANCE of INTRACELLULAR BACTERIA
TUMOR ERADICATION
CYTOKINE PRODUTION: mostly IFNg -> activates phagocytosis

contain granules -> modified lysosomes, contain perforin and granzymes
maturation and differentiation mediated by DCs (co-stimulators)

98
Q

Direct killing mechanisms of CD8

A

PERFORIN/GRANZYME: perforin forms pore, GrzB entry (ser protease)
- cleavage of Bid -> mitochondrial cytochrome c -> Caspase 9 -> apoptosis
- Caspases 3 and 7 activation -> apoptosis
- SET cleavage -> translocation of nuclease -> DNA breakage

FAS-DEPENDENT: FasL on CTL, Fas n tumor/infected cell
- Caspae 8 recruitment and activation
- Casp 8 cleaves Bid (mt cyt c) and Casp 3&7 -> apoptosis

GRANZYME/GASDERMIN:
- GrzA cleaves GSDMB
- c-GSDMB unnecessary, n-GSDMB formes pore in cellmembrane -> cell lysis

99
Q

Killing via Perforin/Granzyme

A

direct killing mechanism of CD8

PERFORIN/GRANZYME: perforin forms pore, GrzB entry (ser protease)
- cleavage of Bid -> mitochondrial cytochrome c -> Caspase 9 -> apoptosis
- Caspases 3 and 7 activation -> apoptosis
- SET cleavage -> translocation of nuclease -> DNA breakage

100
Q

Killing via Fas

A

direct killing mechanism of CD8

FAS-DEPENDENT: FasL on CTL, Fas n tumor/infected cell
- Caspae 8 recruitment and activation
- Casp 8 cleaves Bid (mt cyt c) and Casp 3&7 -> apoptosis

101
Q

killing via Gasdermin

A

direct killing mechanism of CD8

GRANZYME/GASDERMIN:
- GrzA cleaves GSDMB
- c-GSDMB unnecessary, n-GSDMB formes pore in cellmembrane -> cell lysis

102
Q

Indirect killing mechanism of CD8

A

cytokine secretion recruiting other cells to mediate killing
indirect and unspecific destruction of cells

IFNg: produced by CTLs
- stimulates ROS and NOS production by macrophages
- elevated MHC I and II expression
- increased activity of immunogenic proteasome -> elevated susceptibility to CD8s

103
Q

CD8 differentiation

A

requires 3 signals -> MHCI interaction, co-stimulators and cytokines
essential are the CROSS-PRESENTING abilities of cDC1 (licensed by CD4) -> allows incorporation of infected cells/tumor/peptides and their presentation on MHCI

important cytokines:
- IL2: GF -> proliferation and diffeerentiation into CTLs and memory T
- IL12 & IFNg: stimulate differentiation
-> IL2, IL12 and IFNg als important for TH1 differentiation (usually co-activated)

  • IL15: survival of Tm CD8
  • IL21: from TFH -> induction of CD8 memory formation and prevention of exhaustion
104
Q

cytokines for CD8 differentiation

A
  • IL2: GF -> proliferation and diffeerentiation into CTLs and memory T
  • IL12 & IFNg: stimulate differentiation
    -> IL2, IL12 and IFNg als important for TH1 differentiation (usually co-activated)
  • IL15: survival of Tm CD8
  • IL21: from TFH -> induction of CD8 memory formation and prevention of exhaustion
105
Q

phases of CTL response

A

ACTIVATION: clonal expansion, acquisition of effector functions
EFFECTOR: killing
DEATH: apoptosis-induced reduction of CTL numbers
MEMORY: persistent Ag-experiened CD8 -> dependent on CD4 help (IL2, IL15 and IL21)

106
Q

CD8 T cell exhaustion

A

by prologed Ag exposure without clearance
induces phenotypical changes -> downregulation of IFNg and porliferative potential, upregulation of inhibitory markers (PD-1)

PM3 - Infection and immunity (9 decks)

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