T-Cell Mediated Immunity Flashcards
What are the 2 signals of Lymphocyte Activation?
- Antigen binding to antigen receptor (MHC –> TCR)
2. Molecule induced by innate response (costimulator, complement fragment) binding to its receptor
When the 2 signals are provided, what happens?
Lymphocyte proliferation and differentiation
Adaptive Immune Response
Name the effector function of T-Helpers.
Activation of macrophages, B-cells, and other cells
Name the effector function of cytotoxic-T cells.
Killing of infected “target cells”, macrophage activation
Describe the overall mechanism of T-helpers.
When an APC travels to a lymph node, Th binds to MHC Class 2 and upregulates CD40L expression.
CD40L binds to CD40 on APC leading to greater expression of MHC and greater activation of Th (Co-stimulation).
After activation, cells dissociate and Th-cell proliferates. Matures into Effector, Memory, and Regulator cells.
Effector Th stimulates B-cells (Th1), Macrophages (Th2), and Cyt-T (Th2)
Describe the overall mechanism of Cyt-Ts.
When an APC travels to a lymph node, Cyt-T binds to MHC Class 1 and upregulates CD40L expression. CD40L binds to CD40 on APC leading to greater expression of MHC and greater activation of Cyt-T (Co-stimulation).
After activation, cells dissociate and Cyt-T proliferates. Travels to area of infection. Identifies infected cell, which displays Ag on MHC Class 1 and is activated. Cyt-T destroys infected cell through apoptosis. Phagocyte digests remains.
What is found on the surface of a Naive T-cell?
CD4 or CD8, CD28 HLA/MHC Class 1 TCR complex + CD3 LFA-1 and VLA-4 Adhesion molecules Chemokine receptors
Naive T-cells are activated by what cell?
Dendritic Cells (DC)
Memory T-cells are activated by what cell?
B-cells and Macrophages
How do T-cells enter the lymphoid tissue? Be Specific.
They enter through the HEV in the cortex. They weakly adhere to HEV by selecting. T-cells have L-selectin, which binds to L-selectin ligand on HEV.
The CCR7 on the T-cell will then bind to CCL19/21, which turns the integrin receptor from a low-affinity to high-affinity state.
The integrin (LFA-1) on T-cell binds to ICAM-1 on HEV.
How do T-cells leave the lymphoid tissue? What happens when it enter the peripheral venule? Be Specific.
They leave through Efferent lymphatic vessels. They leave with S1P (modulation of CCR) on S1PR1.
Once they reach the peripheral tissue, E/P-Selectin will bind to its ligand on venule. CXCR3 will then bind to CXCL10 or others. Changes affinity state of integrin.
Integrin (LFA-1 or VLA-4) binds to ICAM1 or VCAM-1.
Name the accessory molecules responsible for antigen recognition, signal transduction, and adhesion on T-cells.
Antigen Recognition: TCR –> CLASS 2 MHC
Signal Transduction:
CD3 (with ITAM domains)
CD4 –> CLASS 2 MHC (B2)
CD28 –> B7/CD80 (antigen presenting cells)
Adhesion:
LFA-1 –> ICAM-1
What accessory molecules on T-cells inhibit Signal transduction?
CTLA-4 –> B7/CD80
PD-1 with ITIM –> PDL-1/2
CTLA4 is constitutively expressed on T-regs (competitively interacts with CD80), but sequestered on mature, naive T-cells.
When an Antigen is presented to a T-cell, how does integrin activity change? Explain.
In normal conditions, without Ag, the integrin is in a low-affinity state so there is weak adhesion and no t-cell response.
When Ag is presented, Ag-recognition as well as chemokines release changes integrin affinity state from Low to High. This results in clustering of integrins leading to strong T-cell-APC adhesion and T-cell response.
What happens during T-cell activation? (Exclude adhesion)
Antigen recognition happens by interaction between MHC Class 2 and TCR + CD4
CD40L expression is upregulated on T-cell and binds to CD40 (constitutively expressed on APC), leading to APC activation.
B7/CD80 expression is upregulated on APC and binds to CD28 (constitutively expressed on T-cell). APC also releases cytokines (IL-12). Combined, these enhance T-cell activation and proliferation.
Explain in more detail T-cell activation inside T-cell.
The immunological synapse forms.
2 tryosine kinases are activated:
FYN and LYK (found on CD4/8) = phosphorylate ITAMs, which recruit Zap-70 on zeta chain. Activation of Zap-70 leads to activation of PLCy1. It also leads to the activation of PI3-Kinase and GDP/GTP exchange factor from adaptor proteins.
What happens with the activation of PLCy1?
Cytosolic Ca2+ increased –> increase in calcineurin –> NFAT (transcription factor - nuclear factor activated T-cells)
Diacylglycerol (DAG) increased –> PKC –> NF-kB and AP-1 (transcription factor)
What happens with activation of GTP/GDP exchange factor?
GTP/GDP exchange on RAS and RAC –> ERK, JNK –> NF-kB, AP-1
What happens with activation fo PI3-Kinase?
Activation of PI3-Kinase –> PIP3 –> Akt, mTOR –> increased protein synthesis and NF-kB, AP-1
What cytokine does NFAT up regulate?
IL-2
Activation of T-cells triggers a cascade of protein production. Can you name them and when they start to appear?
Transcription factors c-FOS and c-Jun start being expressed in minuets. c-Myc in hours.
CD40 ligand and FAS ligand are expressed in hours
IL2 is expressed in hours along with IL2Ra (CD25); IFN-y and IL-4 can takes days
What happens when T-cells bind to Ag without binding to co-stimulatory ligands or cytokine support?
It will not become activated. It becomes TOLERANT (unresponsive or anergic).
Maybe one reason why self-ags are not attacked.
What are the cytokines produced by T-cells?
IL-2, IL-4, IL-5, IL-17, IL-22, also IL-10
IFN-y
TGF-B
What is the action of IL-2?
Secreted by ACTIVATED T-cells
Responsible for T-cell proliferation and regulatory t-cell survival
What is the action of IL-4?
Secreted by CD4-Ts and Mast cells
Responsible for B-cell switching to IgE
What is the action of IL-5?
Secreted by CD4-Ts, Mast cells, Innate Lymphoid cells
Responsible for the activation of eosinophils
What is the action of IL-17?
Secreted by CD4-Ts and other cells
Responsible for the stimulation of acute inflammation
Also has some IL-22 function
What is the action of IL-22?
Secreted by CD4-Ts, NK cells, Innate Lymphoid cells
Responsible for the maintenance of epithelial barrier function
What is the actin of IFN-y?
Secreted by CD4-Ts, CD8-Ts, NK cells
Responsible for activation of classical macrophages against intracellular microbes.
Activated B-cells to stimulate complement binding and class switching
Stimulates Class 2 MHC and CD80 expression.
What is the action of TGF-B?
Secreted by CD4-Ts and other cells
Responsible for the inhibition of T-cell activation; differentiation of regulatory T cells
What is the action of IL-10?
Secreted by T-regs and alternative macrophages
Same action as TGF-B, inhibition fo T-cell activation
How does Il-2 promote proliferation?
It is an autocrine signal. IL-2 secreted by an activated T-cell will bind to IL-2Ra (CD25) on the same cell. IL-2R is constitutively expressed as low affinity receptor. Binding promotes proliferation and differentiation.
Explain Cross-Presentation.
APCs (DCs) can present CD4s AND CD8s. IL-2 released by activated helper-Ts can help skip multiple steps in Cyt-T activation leading to water expansion & differentiation.
Explain Trapping.
Naive T-cells have been presented an Ag within 2 days. During this time, CD69 expression is increased. It binds to S1PR1 and prevents migration of T-cells out of efferent lymphatic vessels. This gives them enough time to proliferate and differentiate. After 5 days, the effector cell can emigrate out.
**Cyt-T cells will emigrate immediately, but T-helpers will stay to activate B-cells.
Describe Th1.
Proliferate in response to IL-12 (DC/macrophages) and IFN-y (NK-cells)
Release cytokines that activate Macrophages (IFN-y), also DCs and NKs. Also secretes IL-2.
Host defense: Intracellular pathogens
Role in disease: Autoimmunity, chronic inflammation
What happens intracellularly in a Naive T-cell after interaction with IFN-y and IL-12?
IL-12 activates transcription factor STAT4. IFN-y activates STAT1, which turns into T-bet. Both involved in production of IFN-y, which can self-amplify cell and differentiate into Th1 cells, which secrete IFN-y and IL-2. (Also TNF-a)
Describe Th2.
Proliferates in response to IL-4 (Mast cell).
Secretes IL-4, IL-5, IL-13 to activate Eosinophils. Also to activate mast cells and alternative macrophages.
Isotype class switching to IgE in B-cells
Occurs in response to allergens and helminths
Also–> Mucus production, Peristalsis, IgA production
What happens intracellularly in a Naive T-cell after interaction with IL-4?
IL-4 binding activates STAT6. STAT6 and GATA3 act as transcription factors to produce IL-4 and differentiate into Th2.
Describe Th17.
Proliferates in response to IL-1, IL-6, (TGF-B?).
Secretes IL-17, IL-22 to recruit and activate Neutrophils.
Host defense: Extracellular bacteria and fungi
Role in disease: Autoimmunity; inflammation, leukocyte recruitment, important in barrier function and neutrophil activation
What happens intracellularly in a Naive T-cell after interaction with IL-1/6 and TGF-B?
IL-6 activates STAT3, TGF-B activates RORyt.
Describe Tfh.
Secretes IL-21 (and IFN-y or IL-4) to target B-cells for antibody production
Host defense: extracellular pathogens
Role in disease: Autoimmunity (autoantibodies)
Describe the Migration of Activated Th cells.
Activation occurs in the medullary area with antigen presentation
CCR7 expression decreases, CXCR5 increases –> migration of activated T-cells to EDGE of follicular zone where B-cells are
Activated T-cells start expressing CTLA-4
Cytokines vs. Class Switching. What happens?
When adding mitogen (LPS) to Naive B-cell, class switching does not happen.
But when you add IL-4 + LPS, you have class switching producing IgG1 and IgE
TGF-B + LPS –> IgG2b, IgA
Describe T-Regulatory Cells.
CD4, CD25 Influenced by IL-2 and TGF-B Secrete IL-10 and TGF-B Constitutively express CTLA-4 and CD25 CTLA-4 binds to CD80 and shuts down IL-2 production However, CD80 binds more avidly to CD28 Transcription factor = FOXp3
Describe Gamma Delta T cells.
Less than 5% of T-cells
Found in epithelial boundaries
Ag restricted - limited diversity of peptides recognized, but can recognize NON-PROTEIN Ag
Why is a predominant Th2 response to intracellular microbes bad?
It can lead to poor disease outcomes. This is because Th2 cell inhibit microbial activity of macrophages and instead active alternative macrophages.
In peripheral tissue, no every T-cell that enter the area is specific for that Ag. Why?
The selectins and chemokines are not antigen-specific. So you will have multiple T-cells enter the area. Those that are specific stay. Those that aren’t leave.
How are Ag-specific T-cell retained in the peripheral tissue?
New selecting and integrins are expressed upon activation that help retain the T-cells.
VLA –> ICAM and Fibronectin
P & E Selectin ligands
CD44 –> hyaluronan
What cytokines are required by memory T-cells for survival?
IL-7 and IL-15
Describe the production of memory cells.
Naive T-cell will become effector T-cells (CD8 > CD4)
During homeostasis, many of the effector Ts undergo apoptosis, while some become memory T-cells.
Memory Ts express high levels of anti-apoptotic protein, BCL-2
Will require reactivation to regain effector function and can respond more rapidly than naive Ts.
When does T-cell exhaustion occur?
During chronic infection, exhausted T-cells are unable to respond to virus. This is because of the increased expression of CTLA-4 and PD-1. T-cells cannot keep up with virus.
What happens when you transfer “Immune” T-cell to a non-immune individual? What happens when you transfer immune serum?
When you transfer Immune T-cells, you can transfer immunity to intracellular bacteria to the non-immune individual.
However, immune serum does not protect against intracellular microbes. This is because serum has antibodies that cannot reach intracellular microbes.
What is the major difference between effector T-cells and Naive T-cells?
Naive T-cell require co-stimulation via B7-CD28 interaction, while Effector T-cell can respond to Ag without co-stimulation.
What are the two mechanisms of Cyt-T killing?
Granzymes carried by perforins –> activate caspases
FAS (CD95) on target cells binding to FASL on activated Cyt-T –> activates caspase –> apoptosis
What is significant about IFNa/B?
Inhibits replication of viruses
Increases expression of MHC-1 on other infected cells
Enhances NK killing
What is Antibody Dependent Cell-mediated Cytotoxicity?
NKs, macrophages/monocytes, neutrophil, eosinophil
Identify target though IgG antibody
Kill by lytic enzymes, perforin, TNF
What is the evasion mechanism of mycobacteria?
Inhibition of phagolysosome fuse, survives in phagosome
What is the evasion mechanism of HSV (Herpes)?
Inhibition of Ag-presentation - interferes with TAP at ER
What is the evasion mechanism of Cytomegalovirus?
Inhibition of Ag-presentation - inhibition of proteosomal activity or removal of class 1 MHC from ER
What is the evasion mechanism of Epstein-Barr Virus?
Inhibition of Ag-presentation - inhibition of proteosome
Production of IL-10 –> inhibits macrophage activation
What is the evasion mechanism of Pox Virus?
Inhibition of Effector Cell activation –> production of soluble cytokine receptor that competes with and prevents cytokine activation of effector cell
