What is an Epitope?
The part of an antigen that is recognized by lymphocyte antigen receptors (also known as antigenic determinant)
What are the domains of TCR and BCR receptors? (2)
Constant Region and Variable Region
What causes the proliferation of T cells from the lymphoid progenitor? Where does this occur?
IL-7 in the bone marrow
Where does T-Cell induction take place?
In lymphatic tissues (lymph nodes or the spleen)
Does the constant region of TCR or BCR change?
BCR constant region: can change TCR constant region: fixed
What does the TCR need to do to get passed the FIRST checkpoint during maturation?
Express the variable and constant region of the beta chain
What does the TCR need to do to get passed the SECOND checkpoint during maturation?
Express the variable and constant region of the alpha chain
What are the recombination events that lead to the beta chain of TCR?
1st recombination event: D and J recombination
2nd recombination event: V with DJ
3rd recombination event: VDJ with the Constant region Note: many different types of V, D and J
What are the recombination events that lead to the alpha chain of TCR?
1st recombination event: V with J
2nd recombination event: VJ with the Constant region Note: many different types of V and J
Where is most of the variability found in the TCR alpha and beta chains?
3 regions of hyper-variability in both chains CDR1, CDR2, CDR3
What are the mechanisms of antigenic diversity for the TCR and BCR? (2)
Combinatorial Variability Junctional Variability
What is Combinational Variability?
TCR and BCR variability caused by variation among possible V-D-J (beta chain) and V-J (alpha chain) exon combinations
What is Junctional Variability? (3 mechanisms)
TCR and BCR variability caused by modifications to the genes during the recombination process. 3 mechanisms: 1) Removal of nucleotides 2) Addition of nucleotides by TdT enzyme 3) Strand repair
What is the TdT enzyme? What would a mutation to the TdT enzyme cause?
adds nucleotides to TCR or BCR receptor gene - contributes to TCR or BCR variability Mutation: immune-compramise
What is the FIRST SIGNAL in T Cell activation?
TCR and CD4/CD8 co-receptor recognize MHC/antigen complexes presented by APC's
What is LFA1? What does it bind to?
LFA1 is a T cell intagrin that increases its affinity when the TCR recognizes an antigen/MHC complex. Binds to ICAM-1 on the APC cell surface
What is CD4?
CD4 is a TCR co-receptor that INDEPENDENTLY recognizes MHC Class II
What is CD8?
CD8 is a TCR co-receptor that INDEPENDENTLY recognizes MHC Class I
What do CD4+ T-Cells differentiate into?
Helper T Cells
What do CD8+ T-Cells differentiate into?
Cytolytic T Lymphocytes (CTLs)
How many TCR/co-receptors need to be engaged in order to activate naive T cells? (for the first signal)
2 or more
What is the SECOND SIGNAL in T Cell activation?
T cell CD28 needs to interact with B7, a co-stimulatory molecule on the APC cell surface.
What is CD3?
CD3 is a signaling receptor expressed on ALL T cells. Used as a marker.
What is ITAM?
Activating signal on T cells, part of CD28
What is CD28?
T cell co-stimulatory molecule that interacts with B7 on the APC cell surface. Is the second signal in T Cell activation. Occurs EARLY in the process.
What is CTLA4?
T cell co-stimulatory molecule that interacts with B7 on the APC cell surface. However, it INHIBITS the T-Cell activation and occurs LATE in the process
What is ITIM?
Inhibiting signal on T cells, part of CTLA4
What is ICAM-1?
On the APC cell surface, binds to LFA-1 on T Cell
What is PAMP? Where does it bind? What does it Cause? (3)
What: Pathogen associated molecular patterns
Where does it bind: receptors (toll-like) on dendridic cells or macrophages
What does it cause:
Upon digestion of pathogen:
1) Upregulate co-stimulatory molecule B7
2) Increase levels of MHC
3) Secret cytokines
Once a T-Cell is activated, how does proliferation occur? Genes expressed? (3) When it begins and how long it takes? CD4 expansion? CD8 expansion?
Genes produced: IL-2 cytokine (secreted) and IL2R(alpha) chain - this establishes the high-affinity receptor so that only activated cells will proliferate When it begins/how long it takes: starts 1-2 days after activation (3-4 days to proliferate before it detaches from complex) CD4 expansion: 100 - 1000 fold during infection CD8 expansion: 10,000 fold (10-20% of leukocytes during infection)
What genes are expressed by an activated T-cell and what are their roles? (3)
1) IL-2 cytokine - secreted by the T-cell and has autocrine activity to stimulate proliferation
2) IL2R(alpha) chain - a chain of the IL-2 receptor that establishes its high affinity so that only activated cells will proliferate upon IL-2 release
3) CD40L - binds to CD40 on APC cells providing an amplification signal to maintain APC immune response.
How do CD4+ T cells differentiate into TH1 cells? Cytokine? (2) Microbe? Effect? Role in disease? (2)
Cytokine: IFNy, IL12
Microbe: intracellular bacteria
Effect: activate macrophage --> kill bacteria
Role in Disease: autoimmune, tissue damage associated with infection
How do CD4+ T cells differentiate into TH2 cells? Cytokine? Microbe? Effect? Role in disease?
Effect: Activate B cells --> secrete antibodies to parasites and allergens
Role in disease: Allergies
How do CD4+ T cells differentiate into TH17 cells? Cytokine? (3) Microbe? (2) Effect? Role in disease?
Cytokine: TGF-B, IL6, IL23
Microbe: Extracellular bacteria and fungi
Effect: Activates PMNs --> kill bacteria and fungi
Role in disease: Organ specific autoimmunity
How do effector T cells recognize antigen?
Only needs the first signal to recognize antigens: TCR and CD4/CD8 co-receptor recognize MHC/antigen complexes presented by APC's
Generally, how do effector T cells know where to go to fight infection?
The inflammatory response releases cytokines TNF and IL-1 and chemokines that bind to the endothelial cells and increase in concentration at the site of infection T cells have high-affinity forms of LFA-1 and VLA-4 that bind to the endothelium at the site of infection
What is the role of L-selectin, E-Selectin, and P-Selectin in the immune response?
L-selectin: effector T-cells lose the expression of L-selectin, which prevents it from migrating back to lymph (along with CCR7)
E and P-Selectin: Effector T-cells increase expression - increase ability to migrate to site of infection (along with CXCR10)
How is the site of infection marked? (3)
1) cytokines (TNF and IL1) and chemokines are released by macrophages 2) vasodialation and increased vascular permeability cause redness, heat and swelling 3) inflammatory cells migrate into tissue releasing mediators that cause pain
What cytokines are released at the site of infection? (2)
TNF and IL-1
What types of T cells will go towards the site of infection?
ALL effector T cells, recognizing an array of antigens, will become concentrated at the site regardless of which antigen they recognize.
What T-Cell receptors mediates trafficking to lymphatic tissue? (2)
CCR7 and L-selectin
What T-Cell receptors mediates trafficking to peripheral tissue? (2)
CXCR10 and E/P-Selectin
What is the role of TH1 cells? Produce? Express? Functions? (3)
Functions: 1) induce isotype switching in B Cells
2) Increase microbial killing capacity of phagocytes (marcrophages and PMNs)
3) induce b7 from APC so that CD8 cells can differentiate into CTL
What is the response of an activated macrophage? (3)
1) production of reactive oxygen spcies
2) Secretion of cytokines (TNF, IL-2, IL-12)
3) increased expression of MHC molecules and costimulators
What is the positive feedback loop between TH1 cells and marcrphages and how do you stop it?
1) TH1 cells secrete IFN-y cause macrophages to secret IL-12
2) IL-12 causes CD4+ T Helper cells to differentiate into more TH1 cells
To stop it: kill/remove all pathogens
What is the role of TH2 cells? Produce? Functions? (4)
Produce: IL-4, IL-5, IL-13, IL-10
Functions: 1) induce isotype switching in B cells to produce antibodies (IgE is main one)
2) Increase tissue repair processes of marcophages
3) inhibit macrophage killing
4) Activate eosinaphils
What cytokine from what cell activates eosinophils?
IL-5 from TH2 cells
How do the functions of TH1 cells and TH2 cells interact?
The functions "do not get along". IL-4, IL-10 and IL-13 from TH2 cells inhibit macrophage killing, therby counteracting the effects of TH1 cells, which release IFN-y and TNF to increase macrophage killing
What is the role of TH17 cells? Produce? Functions? (3)
Produce: IL-17, IL-22
Functions: 1) stimulate inflammation increase recruitment of PMNs, monocytes to sites of infection (early stages of inflamation)
2) Maintain epithelial barrier integrity
3) stimulate antimicrobial peptides to kill bacteria
What does IL-17 do? (2) What cell releases it?
TH17 secret IL-17
IL-17 increases the inflammation response and causes the secretion of antimicrobial peptides
How do CTL cells kill?
Secretes: Perforins: creates pore in cell Granzymes: serine protease which activates apoptosis in infected cell Fast Ligand: induces apaptosis by binding fas receptor on target cell
How does CTL get activated from naive CD8 positive T Cells? (2)
Direct: Recognize antigen/MHC Class I complex (first signal) plus HIGH levels of costimulatory molecules (2nd signal - CD28 from T-cell binds with B7 from APC)
Indirect: First signal is normal but second signal not adequate. TH1 cells express CD40L and secrete IFNy which upregulate the co-stimulatory molecules (more B7 to provide second signal)
What is Toxic Shock Syndrome?
A bacterial "superantigen" activates T cells by binding outside binding cleft of many MHC molecules, bypassing the specificity of MHC molecules. Massive unregulated release of cytokines leads to a NON-CLONAL expansion of T cells. Symptoms: Hypotension, change in vascular permeability, change in live function
What types of antigens do BCR and TCR recognize?
TCR: Peptides BCR: protein, lipid or lipoprotein