Immunology 7- Effetor T lymphocytes

Question 1

Summarise T cells

Answer 1

T cells mature in the thymus

The receptor (T cell receptor :CD3) remains membrane bound

Recognise specially processed fragments of protein which are presented to them by target cells. T cell receptor recognises combination of peptide and MHC

Two families CD4 (helper) and CD8 (killer)

Question 2

Describe cell-mediated immunity

Answer 2

Cell-mediated immunity is mediated by effector T cells and their secreted products (cytokines, perforins, granzymes).

Question 3

Define the different types of T cells and target cells

Answer 3

Naïve T cells:
mature recirculating T cells that have not yet encountered antigen

Effector T cells:
encountered antigen, proliferated and differentiated into cells that participate in the host defense

Memory T cells:
Encountered antigen, contracted, ready to respond to future infections.

Target cells:
Cells on which effector T cells act

Question 4

Why do we need a cell-mediated response

Answer 4

Sometimes Antibody is insufficient

Some pathogens are intracellular – hidden in the cell (TB, malaria, HIV etc etc)
Organisms evolve to escape antibody recognition – either by changing shape (influenza) or by coating antigen in carbohydrate (HIV) or producing decoy antigens (RSV)

In these cases T cell mediated immunity is required

Question 5

What does cytokine secretion by Th1 lead to

Answer 5

Macrophage activation — killing of ingested microbes

Inflammation

Question 6

Why is co-stimulation necessary

Answer 6

To limit off target reactions.

Question 7

Describe the role of APC in T cell activation

Answer 7

Dendritic cells (DC) are the model antigen presenting cells (APC) for initiation of a T cell response

DC exist in tissues (surveillance) acquire antigen, move to lymph nodes (needs activation by PAMP/ PRR)

In lymph nodes, DC mature and then present antigen on MHC

T cells detect antigen via TCR and mature to effector T cells
Co-stimulation- cluster of receptors on the surface on APC, often CD40 or 80, usually interact with CD28 on T cells.

Question 8

Where are intracellular pathogens processed

Answer 8

The cytosol

Question 9

Where are extracellular pathogens processed

Answer 9

Endosomes

Question 10

Describe the role of MHC in disease susceptibility

Answer 10

Important for disease susceptibility e.g. HLA-B57 is protective against HIV (since it presents an HIV epitope that alters viral fitness)

Question 11

Which 3 arms of immunity can APC direct

Answer 11

The APC is crucial to directing 3 arms of antiviral cognate immunity – CD8+ CTLs, CD4 T-helper cells, and B-cells for antibody production.

Question 12

Describe the normal migration of T cells

Answer 12

Recirculation increases likelihood to encounter antigen

Lymphocytes recirculate
from blood and lymph to lymphoid organs.
Enter lymph nodes through specialized areas in post-capillary venules called high-endothelial venules (HEV)

Question 13

What happens once the T cell is activated

Answer 13

Activation changes the passage of the T cell through the body, different chemokine addresses, move from lymph to site of infection, the T cells also proliferate (clonal expansion) and differentiation into effector cells.

Question 14

Describe priming of T cells

Answer 14

The effector cells are said to be antigen primed, and this process is referred to as priming the T cells. These primed effector T cells undergo several changes, including expression of new cells surface molecules such as CD154 (CD140 ligand) and various adhesion molecules.

Question 15

Describe the end result of the T-cell response

Answer 15

The end result is a vigorous T cell response and destruction of the pathogen. Most of the activated T cells die by apoptosis, restoring homeostasis to the T cell pool. A few effector cells mature into memory T cells, which can respond faster and more effectively upon reencountering antigen.

Question 16

Summarise the phases of cell mediated immunity

Answer 16

Cell infected
DC collects material
MHC:peptide 
TCR interaction
.Naïve T becomes effector
. Effector cell  sees MHC:Peptide on infected cell
Performs function
 Effector pool contracts to memory

Question 17

Explain the 3 signal model

Answer 17

3 Signals Required

Antigen Recognition
Co-stimulation
Cytokine Release

This licenses the cell to respond

Question 18

Summarise the effector functions of T lymphocytes

Answer 18

Cell mediated cytotoxicity (CD8)
T helper cells (CD4):
Macrophage activation
Delayed Type Hypersensitivity
B cell activation
Regulation

Question 19

Describe the basic role of CD8 (Cytotoxic lymphocytes)

Answer 19

Cytotoxic T cells destroy target cells such as virus infected cells or tumours
Recognise MHCI: Peptide Complexes

Question 20

Explain what happens when CD8 binds to the MHC

Answer 20

When binding to their specific antigenic peptide:self-MHC complexes, TCRs and their associated coreceptors cluster to the site of cell-cell contact.
Clustering of TCRs then signals a reorientation of the cytoskeleton that polarizes the effector cell to focus the release of effector molecules at the site of contact with the target cell.
CTLs contain lytic granules (red) which contain cytotoxic molecules. In the polarized T cells the secretory apparatus becomes aligned toward the target cell and the content of the lytic granules is secreted.

Question 21

Describe cell-mediated cytotoxicity

Answer 21

• Cytotoxic T cells (CTL) kill their targets by programmed cell death = apoptosis
• Apoptosis is characterized by fragmentation of nuclear DNA
• CTL store perforin, granzymes, granulysin in cytotoxic granules
• granules are released after target recognition
• perforin molecules polymerise, form pores in the target cell membrane
• FasL (on CD8) can induce cell death by interacting with Fas on target cells

Question 22

What happens to the CD8 T cells once they kill the target cells

Answer 22

They dissociate from the target cell and are recycled.

Question 23

Why are CD8 T cells important

Answer 23

Escape mutants from HLA-B57 patients affect fitness of the virus.
When transmitted to HLA-B57 negative patients this reverts to the fitter virus
Driving viral evolution

Question 24

Describe CD4 cells

Answer 24

 critical in host defense (numerous infections
in HIV+ patients with low CD4+ T cell counts)
 Naïve CD4+ T cells can differentiate into distinct subsets after antigen encounter
 Produce restricted cytokine patterns to shape the downstream response

 Range of effector functions:
Macrophage activation
Delayed Type Hypersensitivity
B cell activation
Regulation

Question 25

What is the basic role of CD4 cells

Answer 25

T Helper cells produce cytokines (a family of inflammatory mediators). Cytokines have diverse actions on a wide range of cells Cytokines influence the outcome of the immune response

Question 26

Describe T helper subset functions

Answer 26

T helper 1 cells (Th1):  Produce Interferon gamma  Boost intracellular immune response Good in viral infections T helper 2 cells (Th2):  Produce IL4, IL-5, IL-13  Boost anti-multicellular organism response (parasites) Follicular helper T cells (Tfh):  Produce IL-21, reside in B cell follicles  essential for generation of isotype-switched antibodies Th17 cells: secrete IL-17 in autoimmune diseases such as arthritis Important for control of bacteria NB other Th cells defined by cytokines e.g. Th9 (IL-9) and Th22 (IL-22) Treg: T cells that regulate the activation or effector functions of other T cells natural and induced regulatory T cells necessary to maintain tolerance to self antigens

Question 27

What are T helpers defined by

Answer 27

T helpers are defined by the cytokines they produce and the transcription factors they use

Question 28

Describe macrophage activation

Answer 28

Inflammatory Th1 effector cells activate macrophages to promote killing of intracellular pathogens (mycobacteria, leishmania, etc.) Activated macrophages express increased levels of CD40 and TNF-a receptors, and secrete TNF-α which synergises with IFN-γ in the induction of antimicrobial effector mechanisms. Some cross talk between T cell and macrophages by cytokines ( IL-1,IL-12).

Question 29

What determines the pathway that CD4 T cell follows

Answer 29

Which pathway a naïve T cell follows depends on the environment in which it is primed and on any danger signals produced by the innate immune system. For example, if a danger signal is present, such as IL-12 in response to an infection, the T cell is likely to develop into Th1.

Question 30

Describe delayed type hypersensitivity

Answer 30

• can be protective as well as pathological • primary role in defense against intracellular pathogens • eradication of intracellular pathogens • if source of antigen is not eradicated => chronic stimulation, granuloma formation • if the antigen is not a microbe, like in contact hypersensitivity, the DTH produces tissue injury without protection = “hypersensitivity”

Question 31

What happens in delayed type hypersensitivity

Answer 31

Delayed hypersensitivity reactions are initiated when tissue macrophages recognise the presence of danger signals and initiate an inflammatory response. Dendritic cells loaded with antigen migrate to local lymph nodes, where they present antigen to T cells. Specific T cell clones proliferate in response to antigens, which migrate to the site of inflammation. Mediated by pre-existing antigen specific T cells, mainly by inflammatory Th1 cells, CD4+ Th1 cells release inflammatory cytokines that affect blood vessels (TNF-Beta), recruit chemokines and activate macrophages (IFN- gamma), this stimulates most of the damage in delayed hypersensitivity.

Question 32

What can induce DTH reactions

Answer 32

Intracellular parasites (Leishmania), intracellular bacteria (Mycobacteria), intracellular fungi (candida), intracellular viruses (Herpes Simplex), pathogens that are hard to clear. Often causes extensive cell death, granuloma formation, caseous necrosis, autoantigens, and innocuous environmental antigens ( nickel). Local swelling with cellular infiltrates occur 24-72 hours after antigen exposure.

Question 33

Describe the genetic basis of DTH

Answer 33

Because of the need of presentation by T cells, DTH reactions are often associated with specific HLA alleles.

Question 34

Describe the 2 phases of a DTH response

Answer 34

Sensitisation phase: APC activate T cells Effector phase: Macrophage activation (Increase MHC Class 2 expression, increase TNF receptors and increases oxygen uptake)

Question 35

Describe immunological memory

Answer 35

Once the immune system has recognised and responded to an antigen, it exhibits “memory” Immunological memory is also a consequence of clonal selection Antigen-specific lymphocytes (B + T) are the cellular basis Memory responses are characterised by a more rapid and heightened immune reaction that serves to eliminate pathogens fast and prevent diseases. It can confer life-long immunity to many infections Basis for Vaccines

Question 36

Describe the difference between T cells and B cells

Answer 36

In contrast to the B cells, T cells do not undergo isotype switching or affinity maturation

Question 37

Describe memory T cells

Answer 37

Memory T cells go through an expansion and contraction stage Memory T cells differ qualitatively from naïve T cells: Less stringent activation Proliferate faster Express different chemokine receptors

Question 38

Describe the stages of an immune response

Answer 38

Expose, Expand, Contract, Memory

Question 39

Describe T cell exhaustion

Answer 39

Over time – especially in chronic infections CD8 pool contracts – prevents excess damage Problem for cancer/ HIV and CMV where infection has not been fully cleared Less diversity- cannot defend against new pathogens

Question 40

Describe the beneficial and deleterious actions of effector T cells

Answer 40

Recognition of antigenic peptides results in T cell activation and: Clearance of pathogen - antigenic peptide derived from foreign pathogen Pathological reactions can be caused by T cells Autoimmunity - antigenic peptide derived from self protein Rejection (transplants) - antigenic peptide derived from self protein of transplant donor

Question 41

Describe the different types of memory responses

Answer 41

Sometimes immune responses are either: In excess of what is required to clear the pathogen or in the wrong anatomical compartment (Immunopathology) Targeted against self (Autoimmune disease) Targeted against benign Antigens (Allergy)

Question 42

Describe B cell- T cell interaction

Answer 42

Ig+ B cells bind specific antigen. The Ig-antigen complex is internalised, processed and antigenic peptides are presented on the B cell surface in context with MHC 2 molecules. Th cells with specific TCR receptors recognise antigen MHC complex on cell surface. T-B cell interactions trigger expression of CD40 ligand on T cells. The CD40 ligand will interact with CD40 expressed on B cells; T cells release cytokines and B cells express cytokine receptors. The activated B cell will differentiate into Ig secreting plasma cells

Question 43

Describe Th1 associated funtions

Answer 43

``` CD4+ Th1 effector cells activate infected macrophages which present peptides in context with MHC class II molecules on their cell surface. Activate CD8 T cells Th1 effectors produce IFN-γ, IL-2, TNF-α Th1 associated functions Cytokines involved Macrophage activation IFN-γ, TNF-α Delayed type hypersensitivity reaction IL-2, IFN-γ, TNF-α, IL-3, GM-CSF Help for CD8 cells IL-2 Downregulation of Th2 responses IFN- γ ```

Question 44

Describe Th2 associated functions

Answer 44

CD4+ Th2 effector cells are also MHC class II restricted and help B cells to differentiate into antibody secreting plasma cells. Th2 effector cells produce IL-4, IL-5, IL-13 Th2 associated functions Cytokines involved B cell proliferation IL-2, IL-4, IL-5 B cell differentiation and immunoglobulin class switch IL-2, IL-4, IL-5, IFN- γ Downregulation of Th1 responses IL-4

Question 45

Describe Th17 functions

Answer 45

Th-17 cells: a functional subset of CD4+ T cells, produce a particular set of inflammatory cytokines, including IL-17. Th17 cells are protective against some bacterial infections, and also mediate pathogenic responses in autoimmune diseases

Question 46

Describe T reg functions

Answer 46

Regulatory T cells (Treg): Some T cells may differentiate into regulatory cells in the thymus or in peripheral tissue; regulatory T cells inhibit the activation of naïve and effector T cells by contact-dependent mechanisms or by secreted cytokines

Question 47

Describe the expansion- contraction phase

Answer 47

T-Cells do not undergo affinity maturation but memory T-Cells do differ from naïve, as are less stringently activated and proliferates faster

Question 48

Describe pathological T Cell reactions

Answer 48

Sometimes immune responses are either: In excess of what is required to clear the pathogen or in the wrong anatomical compartment (Immunopathology) Targeted against self (Autoimmune disease) Targeted against benign Antigens (Allergy)