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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

humoral adaptive immunity
components and function

A

antibodies produced by B cells
neutralization
phagocytosis
opsonization
complement activation

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

second T cell checkpoint

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

beta selection checkpoint

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

DN3 surface markers

A

CD44- CD25+

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
20
Q

DN2 surface markers

A

CD44+ CD25+

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
21
Q

DN4 surface markers

A

CD44- CD25-

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
25
Lck
kinase phosphorylating ITAMs upon TCR signalling causes recruitment of Zap-70 (LAT - Gr2b - PLC and ras/mapk)
26
signals required for T cell activation
TCR-MHC -> activation CD28-B7 (CD80/CD86) -> survival cytokines -> differentiation
27
co-receptors
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
28
inhibition mechanism CTLA4
competitive inhibition (B7 binding)
29
inhibition mechanism PD-1
recruitment of phosphatases (ITIM)
30
CD62
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
31
CD62L
selectin on immune cells -> binds adhesion molecules on ECs
32
CD62P
selectin on ECs activated by histamins orthrombin -> recognizes neutrophils, monocytes or T cells
33
CD62E
selectin on ECs activated by cytokines -> recognizes neutrophils, monocytes or T cells
34
integrins
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
35
CD11aCD18
integrin LFA-1 on immune cells binding ICAM 1/2 on ECs
36
CD11bCD18
integrin Mac-1 on monocytes, neutophils and DC binding ICAm 1/2 on ECs
37
LAF-1
integrin CD11aCD18 on immune cells binding ICAm 1/2 on ECs
38
Mac-1
integrin CD11bCD18 on monocytes, neutrophils and DC binding ICAm 1/2 on ECs
39
CD49aCD29
integrin VLA-4 on monocytes, naive and effector T cells binding VCAM-1 on ECs
40
CD49bCD29
integrin a4b7 on immune cells, especially gut binding VCAM-1 and MadCAM-1 on ECs in GIT
41
VLA-4
integrin CD49aCD29b on monocytes, naive and effector T cells binding VCAM-1 on ECs
42
a4b7
integrin CD49bCD29 on immune cells, especially gut binding VCAM-1 and MadCAM-1 on ECs in GIT
43
leukocyte extravasation process
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
life cycle naive T cells
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
survival signals for naive T cell population
IL7 or (and?) quinescence mediated by p27kip, KLF2 and Schlafen
46
Surface molecule expression change in effector T cells
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
IL2
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
CD25
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
IL2-R
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
Memory T cells
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
IL7
survival of naive T cell population maintenance and promoting of consttutive low-level proliferation of memory T cells
52
central memory T cells
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
effector memory T cells
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
deletion of T cells + mechanism
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
aging of immune system
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
termination of immune response
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
function of CD4 helper T cells
activation of innate IS activation of adaptive IS cell-mediated immunity licensing DC for cross-priming influence on CD8 T cells
58
CD4 activating innate IS
activate macrophages licensing of APCs (CD40 interaction leads to upregulation of B7) induction of monocyte differentiation (macrophages)
59
CD4 activating adaptive IS
activation of B cells, CD8 T cells killing function themselves
60
licensing DCs
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
CD4 influencing CD8 T cells
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
differentiation of CD4 cells
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
TH1 cells
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
Inductor of TH1
IL-12 and TNF-a, produced by DCs, macrophages and NK cells
65
Product TH1
Products: T-bet, IFNg, TNF
66
Function TH1
Function: antiviral, immunity against extra- and aintracellular bacteria essential for PHAGOCYTE-MEDIATED HOST DEFENCE
67
Properties TH1
Properties: CCR3 upregulated for migration, CCL3 & 4 secretion for additional recruitment of myeloid cells
68
Consequence of loss of TH1
leads to increased Th2 development -> increased IL10 and IL4 -> inhibits microcidal function of macrophages -> increased mortality in infections
69
IL12
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
IFNg
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
TH2 cells
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
Inductor TH2
IL4
73
Product TH2
GATA3, STAT6 IL4 and IL13
74
Function TH2
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
GATA3
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
IL4
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
TH17 cells
Inductor: TGFb, IL6, IL23 Products: RORgt, IL17 Function: fight bacteria, fungi and toxoplasmosen, cooperation with TH1 in phagoyte-mediated eliminitation, contrbte to autoimmunity
78
inductor TH17
TGFb, IL6 and IL23
79
product TH17
RORgt, IL17
80
Function TH17
fight bacteria, fungi and toxoplasmosen, cooperation with TH1 in phagoyte-mediated eliminitation, contrbte to autoimmunity
81
RORgt
TF production induced by inflammatory cytokines (e.g. IL1 and IL6) produced by TH17 drives TH17 response with STAT3
82
STAT3
TF activated by inflammatory cytokines (especially IL-6) drives TH17 repsonse with RORgt
83
TGFb
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
IL6
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
IL23
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
TFH cells
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
Inducer TFH
IL21, IL6
88
Product TFH
Bcl6, IL21
89
Function TFH
high CXCR5 expression allows migraion along CXCL13 to lymphoid follicles, critical for GERMLINE CENTER FORMATION
90
Markers TFH
CXCR5, ICOS, PD-1, IL21 and BCl-6 -> all essential for GC development
91
MAIT cells
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
MR1
MHC-related 1 present Ag -> recognized by MAIT cells (cytotoxic and secrete IFNg)
93
gd T cells
on epithelial surfaces bind phospholigands cytotoxic and secrete IFNg
94
CD1-restricted ab T cells
recognize glycolipids only when presented on CD1 by DCs cytotoxic and secrete IFNg
95
CD1
on DC can present Ag (glycolipids) recognize by CD1-restricted ab T cells (cytotoxic and secrete IFNg)
96
Treg cells
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
function of CD8 T cells
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
Direct killing mechanisms 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 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
Killing via Perforin/Granzyme
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
Killing via Fas
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
killing via Gasdermin
direct killing mechanism of CD8 GRANZYME/GASDERMIN: - GrzA cleaves GSDMB - c-GSDMB unnecessary, n-GSDMB formes pore in cellmembrane -> cell lysis
102
Indirect killing mechanism of CD8
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
CD8 differentiation
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
cytokines for CD8 differentiation
- 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
phases of CTL response
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
CD8 T cell exhaustion
by prologed Ag exposure without clearance induces phenotypical changes -> downregulation of IFNg and porliferative potential, upregulation of inhibitory markers (PD-1)