T cell development and Effector function Flashcards
TCR
Very similar to BCR
undergo VDJ recombination
Use RAG proteins
V contains 3 hypervariable regions
no class switching no affinity maturation
membrane bound!
why dont we want TCR to undergo affinity maturation
b/c it increases the liklihood a Tcell would recognize a self peptide
which would cause autoimmune diseases
TCR-MHC interaction
TCR’s recognize as few as 1-3 residues of the MHC peptide complex
compared to antibody/antigen interaction, the binding of TCR to MHC molecules is weak
additional cell surface molecules are necessary for TCR activation
TCR’s must recognize both…
Peptide
AND
MHC molecule
what is missing in the alpha chain of the TCR
Diversity region
T cells whose TCR’s recognize class I MHC peptide complexes …
preserve the expression of CD8
which become cytotoxic cells
T cells whose TCR’s recognize class II MHC peptide complexes…
preserve the expression of CD4
which become T helper cells
Cell-mediated immunity
Combats intracellular microbes
either in:
ingested microbes (phagocytosed and living in vesicles)
viruses (present in cytoplasm)
t cells help the phagocytes kill the microbes they have ingested t- cells help by binding to MHC class I presented on the surface of infected cells
where can T lymphocytes be activated?
Spleen
Lymph node
CD4 or CD8
interacts with MHC II and MHC I
CD3
on all T cells
TCR complex
CD3, TCR and zeta chain
CD28
interacts with B7 molecules
LFA1 and sometimes VLA4
adhesion molecules that are slowing down T cell down so all interaction can occur
LFA-1 interacts with ICAM-1 (on endothelium) for activation lymph nodes
VLA-4 interacts with VCAM-1 (on endothelium) important for getting T cells into peripheral tissues (out of blood)
signal 1 for T -cells
Antigen
MHC class I or II
CD4 or CD8
signal 2
CD28 binding to B7 on APC’s
this induces expression of IL-2 and change in the affinity of the IL-2 receptor–> activation of T cell
after period of time of having T cells activated…. CTL4 comes up and does what?
it is an inhibitory signal
shuts down IL-2 production
binds B7 molecules so it outcompetes the CD28
T cell shuts down
how are CD8 T cells activated differently
involves cross presentation
infected cell is phagocytosed by APC
APC presents antigen which is recognized by CD8 and CD4 cells
dendritic cell presents peptide of class I and II
CD4 T helper cell after it is activated by binding then releases cytokines which help activate CD8
CD 8 cell gets costimulation from APC and from CD4 cell, and can then go on to undergo clonal expansion and differentiation
what is cross presentation
to indicate that one cell type (the dendritic cell) can present antigens from another cell (the virus-infected or tumor cell) and prime, or activate, T cells specific for these antigens.
what is CD40 and when is it produced?
CD40L increases on CD4 T cells after they are activated and interacts with CD40 on APC’s to strengthen adhesion
prolongs APC-T cell contact
What happens after T cell activation
Protein production cascade!
CD40 L IL-2 IL-2 receptor changes to high affinity for IL-2 b/c of expression of IL-2 Ralpha chain leading to proliferation IL-4 IL-5 IFN-gmma TGF-beta
IL-2
survival, proliferation
produced by CD4 and CD8
IL-4
B cell switching to IgE
produced by CD4, mast cells
IL-5
activation of eosinophils
produced by CD4 and mast cells
IFN-gamma
activation of macrophages
Produced by CD4, CD8, NK cells
TGF-beta
inhibition of T cell activation
differentiation of T reg cells
produced by CD4 and many other cell types
effects of blocking CTLA-4?
good to shut off T-cell production
cancer treatment
what does the TCR recognize?
MHC associated peptide antigens and the MHC that is holding the peptide
Once the pre-TCR complex is made what happens…
Once Pre-TCR complex is made is starts to produce signals which promote survival, proliferation and TCR alpha gene recombination and allelic exclusion (so inhibits VDJ recombinase at the second TCR-beta chain locus)
what do class II molecules express
protein antigens that are ingested by APCs from the extracellular milieu into vesicles
thus CD4 + T cells recognize antigens ingested from extracellular microbes
what do class I molecules express
protein antigens present in the cytosol are processed into peptides that are expressed by MHC class I
thus…
CD8 + T cells recognize peptides derived from cytosolic or nuclear antigens
what stimulates the expression of B7 on APC’s
microbes
this leads to fully active T lymphocytes
Activation of CD4 TH1 cells
CD4 T cell CD40 Ligand binds CD40 on Macrophage
IFN gamma from NK cells binds to macrophage
TLR on macrophage binds microbe
all this stimulates IL-12 gene transcription/production
IL-12 stimulates differentiation of CD4+ T cell into TH1 subset
TH1 then produces IFN gamma which stimulates macrophages activation to kill microbes (CLASSICAL)
DTH
Delayed-type hypersensitivity
Macrophages activation by TH1 cells is dependent on antigen -recognition
PPD test looking for DTH response
primary infection
1-2 weeks later elicit challenge with antigen
pt responds 24-48 hours later with raised red area
those T cells and macrophages are influxing into the area, and this leads to the red raised area.
Activation of macrophages by CD4 TH1 subset
CD40 L on CD4 cell binds to CD40 on macrophage
macrophage with ingested microbes presents MHC class II with peptide of microbe
CD4 TH1 cell secretes IFN-gamma which activates the macrophage to:
- produce ROS, NO and lysosomal enzymes
- secrete cytokines (TNF, IL-1, IL-12) (inflammation)
- increased expression of MHC molecules and costimulators
Mechanism of action for CD8 cells
antigen recognition and binding of CTL to target cell
(target cell has microbe in cytoplasm- most often virus)
in the bind it has LFA-1-ICAM-1
CD8 binding MHC II
TCR with peptide and MHC II
CD8 cell is now activated and releases perforin (pokes holes) and granzyme (cleave proteins) which poke holes in the target cell
cell then dies by apoptosis
Cooperation b/w CD4+ and CD8+ t cells
Some APC’s put up both MHC class I and MHC class II so CD4 and CD8 can both bind
IFN -gamma released by CD4 cells can also activate CD8 cells
balance between TH1 and TH2
determines the outcome of intracellular infections
TH1 activates macrophages
TH2 produces IL10, IL-4 and IL-13 which inhibits microbial activity of macrophages
Defect in TH1 leads to…
high TH2 cytokines
allows bacterium that live in phagosomes to escape and divide
