T cells Flashcards
what are the 3 signals do naive cells require
Activation, survival and differentiation
What are the activation signals
CD4 and MHC/ TCR
what are the survival signals
CD80/86 and CD28
Draw interaction of DC and APCs
What is the signal for T cell differentiation
IL-12
what are co-inhibitors of T cells
CTLA-4 to CD80/86
PD-1 - PDL
What are the co-stimulators of T cells
CD28-CD80/86
ICOS-ICOSL
what are main APCs
mature DCs, macrophages and B cells
what ligation signal is optimal for t cell clonal expanssion
CD28-CD80/86
CD28-CD80/86 what does it induce
IL-2 and IL-2r
what does il-2 receptor consist of
alpha, beta and gamma
what does the removal of il-2 on activated t cells cause
cell death
what does il2 and il2r initiate
t cells to enter cell cycle, inducing t cell proliferation
what is icos expressed by
activated CD4+ T cells
what is icos induced by
T cell receptor and CD28 signals.
What does icos regulate
growth, proliferation, survival and induce cytokine production by CD4 t cells
ICOS expression on TFH cells
help B cell responses such as isotype switching through IL-4/IFN-g.
CD40L on T-cells binds to
CD40 on activated APC
whats induced on DC after CD40L stimulation
OX40/OX40L
OX40 signalling important for
T cell survival and homeostasis
supports the generation of memory T cells.
OX40 deficient mice
exhibit reduced CD4 T-cell proliferation in response to viral infection.
What role do B cells play in T cell activation?
resent soluble antigens, including toxins and viruses.
What role do B cells play in T cell activation?
intracellular or extracellular pathogens
Role of Dendritic Cells in T Cell Activation
through peptides and viral antigens, including allergens - deliver all three signals necessary for naïve T cell activation
anergy
lack of co-stimulatory signals
CTLs kill target cells through two primary pathways
Perforin-Granzyme Pathway, Fas-FasL Pathway
Perforin-Granzyme Pathway
CTLs release perforin, which forms pores in the target cell membrane, and granzymes, which enter through these pores and induce apoptosis
Fas-FasL Pathway
CTLs express Fas ligand (FasL), which binds to Fas on the target cell, triggering apoptosis through activation of caspases
Regulatory mechanisms- CLTs
PD-1 and CTLA-4, which can downregulate CTL activity
CTL - Therapeutic strategies
checkpoint inhibitors, aim to enhance CTL responses against tumors by blocking inhibitory signal
Vaccines CTL
stimulate robust CTL responses are also a goal in the fight against chronic viral infections, such as HIV and HBV
CTL
Cytotoxic T lymphocytes
what are the 2 signals needed for CTL
TCR and MHC 1 and co-stimulatory signal: CD28 on the T cell and CD80/86 (B7 molecules) on the APC
CD8+ T cells priming lead to
Clonal expansion, differentiation to kill target cells
what do CTL express
IL-2 receptor=
what chemokines guide ctls to site of inflammation
CXCR3, CCR5
PD-1/PD-L Pathway inhibts CTL by
inhibition of the PI3K/Akt pathway, which is essential for cell survival = cell death, promote the development
PD-1 - tumour microenviroment
high levels of PD-L1 expression on tumor cells can engage PD-1 on T cells= tumor to escape immune surveillance.
clta-4 vs cd80/86
has higher affinity and restricts IL-2 production
autoimmune disorders linked to dysregulated PD-1 &/or CTLA-4
Type 1 diabetes, RA
immunological synapse
t cell and APC interaction
T cell and APC interaction triggers the formation of immune synapse leading to what changes
- Accumulation and segregation of surface molecules
- cytoskeletal polarization
- polarised exocytosis
cytoskeletal polarization
Actin filaments and microtubules align towards the APC
Polarized Exocytosis
polarized towards the AP- secretory vesicles directed to IS
c-SMAC
Enriched with TCR/CD3
p-SMAC
Contains integrins such as LFA-1, which forms a ring around the c-SMAC, providing structural support.
d-SMAC
adhesion molecules like CD4, which stabilize the interaction between the T cell and APC.
what’s the SMACs
central, peripheral, distal
CD45
Interfere with TCR signaling due to its size and phosphatase activity- so only in d-smac and excluded from c-smac
CD45 whats the point
dephosphorylating certain proteins, ensuring TCR signaling is neither too weak nor too strong- preventing inappropriate t cell activation
smac
supramolecular activation molecules
what signals are required for th1
IL-12 and IL-18
what do th1 produce
IFN-γ, TNF-α, and IL-2
th1 combat
intracellular infections, such as bacteria and viruses
how do th1 help combat(4)
activating macrophages, aiding CD8+ T cell function, enhancing antigen presentation, and influencing B cell antibody class switching
IL-18 and IL-12 drive what activation
NK cells
TLR4 ligand
LPS, on gram negative bacteria and DAMPs
TLR 4 function
activation of NF-kB, and release of pro-inflammatory(TNF-a, IL-1, IL-6), upregulates co-stim molecules on APCs
TLR4 in vaccines and therapeutics
upreg could boost the immune response against infections and cancer, downreg could dampen harmful inflammation in diseases like sepsis and autoimmunity. - induce inflam response to vaccine
what disease needs upreg of tlr4
sepsis
il-12/il-12r
activates the STAT4 (Th1)
IL-18 binds to the IL-18 receptor
activation of NF-κB- contributes thfa and ifny production
IFNγ/ IFNγr
STAT1 (Th1)
STAT4/1
promotes Tbet expression
tbet
transcription factor for th1
th1 positive feedback loops
IFNy induce its own production, upregulating IL12 - cell more responsive to IL-12 and il-18
what does th1 upreg
IgG2 (extracellular bacteria) class switching, granuloma formation, macrophage phagocytosis
GM-CSF - released by th1
activates macrophages
th1 and RA
activating macrophages - increase inflammation in RA also IBD
Th2 involved in what responses
Allergen responses (Helminths)
what cells do TH2 activate
eosinophils, basophils, and B cells (IgE)
why cant TH1 see TH2 infections
they (Helminths) dont have LPS
how do they differentiate into th2 and not th1
express lower levels of peptide-MHC (pMHC) and co-stimulatory molecules
what cytokines lead to th2
IL-4,IL-2, IL-33 and TSLP
What do TH2 produce
IL-4, IL-5, and IL-13 (inducing IgE class switching)
what does IgE do
bind to mast cells and basophils= release histamines
ILC2 Activation
activated by IL-25 and thymic stromal lymphopoietin (TSLP)- amplifying Th2
il-5 function in th2
recruits eosinophils, which release cytotoxic proteins that can damage or kill parasites.
IL-13 th2
increases mucus production, which can help to trap and expel helminths and their eggs from the gut.
IL-4 and IL-13 (TH2)
promote tissue repair/ remodelling and wound healing through the activation of M2 macrophages
Necrotic (damaged or dead) epithelial cells release
IL-25/ TSLP (alarmins) and IL-33
examples of helminths
roundworms, tapeworms
Fibrosis
chronic activation of Th2 responses, excessive formation of connective tissue
FcεR1
high-affinity receptor for the Fc region of IgE antibodies
cross-link IgE
cause degranulation of mast cells and basophils= release histamines and inflammatory ctokines
symptoms when IgE bound to mast cells
smooth muscle constriction, increased vascular permeability, edema, and secretion of mucus
examples of tissue remodelling by il-13 and il-4
asthma, chronic allergens
fc region
on igE antibodies
fc binds to
FcεR1
cross-linking
two IgE antibodies bound to the same cell recognize the same allergen- as allergen has multiple identical epitopes
Histamine
Causes vasodilation and increases the permeability of blood vessels
cytokines released by mast cells and basophils
IL-4 and IL-13, TNF alpha (promotes inflammation and recruitment)
another granular content like histamine
Prostaglandins
eosinophils releasein th2 response
release MBP, ECP and EPO (damage paracitic membrane)
Th9 Cells
related to Th2 cells, induced by TGFβ, produce il-9
Th3 Cells
produced by TGFβ, they contribute to mucosal immunity and tolerance and induce IgA production
Th22 Cells
relate to Th17, they produce IL-22 involved in skin homeostatic and inflammation (can be promoted by AH receptor - found in smoke)
Ex-Th17 Cells
former Th17
Tr1 Cells
T cells produce IL-10 and can suppress immune responses. They may produce IFNy-promote immune cells
STAT 6 inhibition
activated by IL-4 inhibits IFNγ production to prevent Th1 differentiation
STAT1 and STAT4 inhibit
(promoted by IFNγ) inhibit Th2 differentiation by suppressing IL-4 production.
wht cells do th2 interact with
ILCs, basophils, eosinophils, mast cells,
macrophages and DCs
what cells do th1 interact with
CD8+ Tcells, NK cells, macrophages and DCs
Th17 produce
IL-17A, IL-17F, TNF (tumor necrosis factor), IL-21, and IL-22
IL-17A and IL-17F
attract neutrophils and other immune cells to the site of infection or inflammation.
Th17 function
fungal pathogens - candidia albicans
IL-21 produced by Th17 cells
supports differentiation of tfh
dysreg of th17 response
leads to RA and MS
what CD defines T cells
CD3
T helper cells (aka CD4 T cells) CDs
CD3+CD4+
CTLs, cytotoxic T lymphocytes (aka CD8 T cells) CDS
CD3+ CD8+
= NKT cells (CD161 is aka NK1.1) CDs
CD3+ CD161+
gamma/delta T cells
innate like - small population of t cells
SCID
severe combined immunodeficiency (too little T cell activity)
Example of SCID
Genes that affect IL-2 (IL-2 fuels TH cell proliferation)
The genes that re-arrange the TCR and BCR
treatment of SCID
- Avoid infection
- Passive transfer of antibodies
- Bone-marrow transplantation
- Gene-therapy to replace defective gene
- Continual antibiotics
what does HIV-1 infect
CD4+ T cells (leads to depletion and death)
HIV-1
Human Immunodeficiency virus 1
what structures is the thymus made from
cortex, medulla, cortico-medullary junction
thymus cortex
largest part of thymus mostly composed of epithelial cells
thymus medulla
contains epithelial cells, macrophages, DC
why do so many cells in thymus die
selection
what are the several key stages of t cell development in thymus
DN, DP, SP
Bone marrow chimeras
allowed identification of CD4 and CD8
TCRαβ^lo
as T cells begin to test their receptors against self-peptides presented by MHC (rearrangement in DP phase)
TCRαβ^+
denote T cells that have successfully undergone the positive selection ( (SP phase CD4^+ or CD8^+)
what are the thymic APC
cTEC, mTEC and mDC
APECED
mutations within AIRE
Sympathetic ophthalmia
to presentation of self-Ag and the immune system attacks the undamaged eye
Mumps/Measles orchitis
Both the mumps and measles viruses can cause inflammation of the testis
Some antigens are (usually) never ‘seen’ by the immune system
eyes and testis
cell-intrinsics
Quiescence (returning to resting state), programmed cell death, memory
cell-extrinsic
Regulatory cells, immune supressive cytokines and drugs
innate regulatory cells
Myeloid derived suppressor cell
