5 - T cells and CMI Flashcards
What can Trichuris suis be used to treat?
Trichuris suisis is found in live ova of pig intestinal helminth and can be used to treat Crohn’s disease (ewwwwww)
What is the mechanism of therapy in Trichuris suis?
The mechanism of therapy might entail the shifting of the predominate TH1-mediated immune response that is involved in Crohn’s disease to a TH2-mediated response that eliminates the parasitic worm
What family are T lymphocytes a part of?
T lymphocytes are a subset of the lymphocyte family, which also includes B cells and NK cells
How large are T lymphocytes?
8 - 10 um in diameter
Can you distinguish between T cells and B cells?
No!
What is the difference between B cells and T cells?
Unlike B cells, T cells only recognize antigens when they are presented by an APC with MHC proteins - this is termed “MHC restriction”)
Describe the path of T lymphocyte maturation
Ontogeny
- Prothymocytes from bone marrow migrate to the thymus (thymocytes)
- Thymocytes then differentiate into mature T cells
- Mature T cells from the thymus travel to peripheral lymphoid organs
- Memory T cells reside in the bloodstream until directed to enter non-lymphoid tissues to elicit cell-mediated immune responses
Where do mature T cells reside?
Peripheral lymphoid organs
Where do memory T cells reside?
In the bloodstream (until they are needed for an immune response)
What are the three types of T lymphocytes?
- T helper lymphocytes
- Cytotoxic T lymphocytes
- Regulatory T lymphocytes
What are the different types of T helper lymphocytes (4)? What is their role?
Called the CD4+ subsets
- TH1 cells
- Cell mediated immunity (IgG can be produced)
- TH2 cells
- Humoral immunity (especially IgE)
- TH17
- Enhances inflammation
- TFH
- Promotes germinal center formation in lymphoid organs
What is the role of cytotoxic T lymphocytes?
Called either CTLs or CD8+ cells
- Function to lyse virus-infected cells
What is the role of regulatory T lymphocytes?
Treg cells which downregulate immunity
What is a TCR?
T cell antigen receptor (TCR)
- The TCR encompasses the proteins on the surface of T cells that allow them to recognize and respond to antigen
How many identical copies of a TCR would you find embedded on a T cell surface?
30,000
What type of genes are rearranged similar to how immunoglobulin genes are?
Genes encoding for the TCR
Is TCR responsible for MHC?
NO!
MHC restriction is a function of CD4+ and CD8
Describe the physical structure of a TCR
T cell antigen receptor structure
- TCRs are found as a heterodimer of disulfide-linked alpha and beta chains
- Each chain has constant and variable regions that are similar to antibodies
- Different antigen specificities are generated by altering variable regions
Which of the two chains (alpha or beta) of a TCR is involved in binding antigen and MHC?
Trick question… BOTH
Is the cytoplasmic tail of a TCR long enough to act as a signal transducer?
No - it requires CD3
How do T cell antigen receptors (TCRs) differ from the immunoglobulin antigen receptors of B cells?
- TCR has a single antigen binding site whereas B cell antigen receptors have two antigen binding sites
- Unlike antibody, TCR is never secreted
CD3 (which is required for the cytoplasmic tails of T cell antigen receptors to be able to act as signal transducers) is composed if several invariant polypeptides… What are they?
Normal stoichiometry
- 1 gamma chain
- 1 delta chain
- 2 epsilon chains
- 2 zeta chains
What is the purpose of phosphorylation sites on the cytoplasmic tails of CD3 (part of TCRs)?
Signal transduction
How do “co-stimulatory molecules” aid in the T cell response?
Co-stimulatory molecules
- Help the T cell to become activated by triggering signal transduction
- CD28 can then bind to B7
- CD40 ligand (CD40L) can bind to CD40
- B7 and CD40 are then expressed on all professional antigen presenting cells
What is CD4? Where is it found?
CD4
- A transmembrane glycoprotein consisting of a single polypeptide
- Expressed on 65% of mature T lymphocytes
- Most CD4-expressing lymphocytes are T-helper cells
- They are present in small quantities on the surface of macrophages
What is the function of CD4?
CD4 is an accessory protein
- Functions as a cell adhesion molecule
- Aids signal transduction
- Restricts T cell responses to recognizing only class II MHC proteins (CD4 binds to invariant regions of class II MHC proteins)
What is CD8? Where is it found?
CD8
- An accessory protein
- Composed of a homodimer or heterodimer
- Most CD8-expressing lymphocytes are cytotoxic T lymphocytes
What is the function of CD8?
CD8 function
- Cell adhesion
- Signal transduction
- Restricts T cell responses to recognizing only class I MHC proteins (CD8 binds to invariant regions of class I MHC proteins)
What four things occur during signal transduction?
- TCR binds to MHC-bound antigen
- Early activation events
- Gene transcription
- Mitosis
During signal transduction, what happens when TCR binds to MHC-bound antigen?
- Clustering of the TCRs with multiple MHC-peptide complexes
- As few as 10 MHC-peptide complexes can trigger T cell activation
During signal transduction, what happens during early activation?
- Phosphoinositide pathway is activated, RAS is activated, and therefore the MAP kinase pathway is activated
- Protein kinase C and other kinases phosphorylate transcription factors
During signal transduction, what happens during gene transcription?
During signal transduction, what happens during mitosis?
- Expands antigen-specific clones to amplify an immune response
- Mitosis is detected 48-72 hours after stimulation through the TCR
What are the two subsets of T helper cells?
TH1 (T helper cell 1) and TH2 (T helper cell 2)
What is similar about the two subsets of T helper cells (TH1 and TH2)? What is different?
Same:
- Both TH1 and TH2 develop from the same antigen naïve CD4+ T cell precursors (called a Th0 cell)
Defferent:
- TH1 and TH2 cells have very different immune functions
What is the role of TH1 cells?
TH1 cells
- Direct the immune response toward cell-mediated immunity
- They do this my producing interferon-gamma (IFN-gamma)
- Also by activating macrophages and CTLs
What do TH1 cells develop from?
Development
- TH1 cells develop from uncommitted naive T cells
- This occurs when the naive T cells receive the proper cytokine signal
The presence of ____________ signals uncommitted naive T cells to develop into TH1 cells instead of TH2 cells during conditions of inflammation
Answer = Interleukin-12 (IL-12)
- This is produced under conditions of inflammation as caused by various bacteria, viruses and other pathogens
What is present during inflammation that encourages the production of interleukin-12?
Macrophages
What is achieved by activating macrophages?
Enhanced microbial killing
What are two ways to stimulate the differentiation and development of cytotoxic T lymphocytes (CTLs)?
- CD4+ helper T cells produce cytokines - this stimulates CTL differentiation
- CD4+ helper T cells enhance the ability of APCs to stimulate CTL differentiation
What is the role of TH2 cells?
TH2 cells…
- Direct the immune response toward IgE production for anti-parasite defense
- Particularly helminth (i.e. worm) infestations
- They do so through the production of IL-4, IL-5 and IL-13
How do TH2 cells develop?
TH2 development
- TH2 cells develop from uncommitted naive T cells when exposed to interleukin-4 (IL-4)
- IL-4 is thought to be produced by mast cells or antigen-activated T cells
When will the immue response take the TH2 pathway instead of the TH1 pathway?
In the absence of inflammation - the immune response will default to the TH2 pathway when no inflammation in present
Are TH1 and TH2 immune responses seen at the same time?
No, not usually
- As a regulatory immune mechanism, there is an antagonistic effect of Th1 and Th2 cytokines, therefore Th1 cytokines inhibit Th2 responses and, conversely, Th2 cytokines inhibit Th1 responses
- Therefore, an immune response usually is dominated by either a Th1 or Th2 response
- Mixed responses can be seen under some circumstances
What are TH17 cells?
Promotors of inflammation
- They do this by producing IL-17 and IL-22
How do TH17 celld develop?
TH17 cell development
- Develop from uncommitted naive T cells when exposed to IL-1, IL-6 and transforming growth factor-beta (TGF-B)
When are IL-1 and IL-6 produced? What do they do?
IL-1 and IL-6
- Produced by dendritic cells during anti-microbial defense
- They are considered to be inflammatory cytokines
- They allow for TH17 cells to develop from naive T cells
What is the source of TGF-B? (the other factor that allows for TH17 cell development)
Transforming growth factor-beta (TGF-B)
- The source of TGF-B includes various cell types
- There is no one specific source
What is the role of IL-23?
- IL-23 serves to stabilize TH17 (a T helper cells that promotes inflammation)
- Also, IL-23 is produced by dendritic cells
Recall the antagonistic effect of TH1 and TH2 cytokines… How are these regulated?
Antagonistic effect of TH1 and TH2 cytokines
- IFN-gamma inhibits the TH2 response
- IL-4 and IL-13 inhibit the TH1 response
Recall that the immune response is usually dominated by either a TH1 or a TH2 response
What are the 3 main functions of a CTL? (cytotoxic T lymphocyte)
Cytotoxic T lymphocyte (CTL)
- Destroys intracellular microbes (viruses and some bacteria)
- Destroys some tumor cells
- Destroys transplanted tissues and organs
Is CTL activation part of the TH1 or TH2 pathway?
CTL activation is part of cell-mediated immunity stimulated by the TH1 cells
How do CTLs recognize endogenous peptides that are presented on class I MHCs?
Antigen recognition through the TCR and the binding of CD8
The CTL killing process is a 5 step process… What are the 5 steps?
- Target cell binding and recognition of class I MHC and antigen
- CTL activation
- CTL becomes activated due to the signal transduction cascade that occurs with TCR binding
- Delivery of the “lethal hit”
- There are two different mechansims (next cards)
- Disengagement from the target cell in order to attack other target cells
- Death of the target cell
There are two mechanisms for delivering the “lethal hit.” What is the primary/principle mechanism?
Principle mechanism
- Perforin facilitates deliver of granzyme B to the target cell cytoplasm
- Granzyme B activates the caspase pathway, which leads to target cell death through the mitochondrial pathway of apoptosis
What is the secondary mechansim for CTL killing by “lethal hit”?
Secondary mechanism
- First, the target cell’s Fas protein will bind to a Fas ligand expressed by the CTL
- This activates the caspase pathway
- Leads to apoptosis of the target cell
