Adaptive Immunity: T-cell Response Flashcards
What is the precursor for T cells?
Common lymphoid progenitor (CLP) cells which originate in the bone marrow
-and then migrate to the thymus where they maturate
What are the 3 main types of T cells?
Cytotoxic T cells (CTL) - Vital in controlling intracellular pathogens
T helper cells
Regulatory T cells - makes sure that the immune system isn’t over activated
What do T helper cells do?
-They regulate the adaptive immune response including activation of immune cells e.g T cells, B cells, Macrophages and dendritic cells
-This activation is mediated by cytokines released by Th cells
What do cytokines do?
They bind to specific receptors on surface of target cells & initiate cell-signalling (hormone-like).
What are interleukins important for?
-Type of cytokine
-Important for tuning the immune response IL-1 IL-2 IL-3 (in order of discovery)
What do CTLs (cytotoxic T lymphocyte) do?
They recognise cells that are infected by intracellular pathogens & induce programmed cell death (apoptosis).
What are the 3 ways that CTLs can induce apoptosis?
- Secretion of TNF (tumour necrosis factor) which binds to TNF receptor
- CTL secretes perforin & granzymes
- Fas ligand (TNF homologue) binds to Fas (TNF receptor homologue)
What do all T cells express?
A cell surface (membrane bound) antigen receptor (TCR) formed by 2 polypeptides – α chain and β chain
Unconventional T cells have antigen receptors formed by gamma and delta chains.
Each T cell has receptor of unique specificity
Does TCR bind to the antigen directly?
No, it will only bind to fragments of antigens (peptides) that are bound to major histocompatibility complex (MHC) proteins on the surface of the target cell.
What are the 2 types of MHC?
Class I and Class II
MHC class I: overall structure similar but α polypeptide is larger and forms complete peptide binding domain β2microglobulin
-(β2m) is not transmembrane domain
What is the structure of MHC II:
slide 13
What does it look like when a T helper cell binds via TCR to an MHC II complex with a peptide?
-Alpha helices (shown in red) along with the peptide are recognised by the TCR
- So its not just the peptide or just the MHC that it recognises, they are recognised by TCR when together.
slide 13 and slide 14
What is CD3?
Complex of 6 transmembrane proteins
Forms part of TCR complex and transmits activation signal
Do CTLs express CD4?
No, but they express CD8 in association with the T cell receptor
What is CD8?
A dimer & type of protein on the plasma membrane of T-cells
TCR of CTL is associated with CD8 which binds to MHC I
What are the differences between MHC class I & II proteins?
MHC class I:
-MHC I expressed by all nucleated cells.
-3 gene loci on chromosome 6: HLA-A, HLA-B, HLA-C. Expressed from both copies of chromosome 6.
-Highly polymorphic – presumably driven by requirement to bind large number of different peptide antigens
CTLs bind to MHC I/peptide complexes.
MHC class II:
-MHC II only expressed by cells involved in immune response: dendritic cells, macrophages, activated B cells and T cells.
-3 gene loci on chromosome 6: HLA-DR, HLA-DP, HLA-DQ. Expressed from both copies.
-Highly polymorphic
-Helper T cells bind to MHC class II/peptide complexes.
What is antigen processing?
The mechanism that breaks down proteins to peptides which may be bound by MHC molecules & exported to the surface.
Where are antigenic peptides presented by MHC class I derived from? What are they recognised by?
-Derived from intracellular pathogens that synthesise or release proteins in the cytosol
-Recognised by CTL’s.
Where are antigenic peptides presented by MHC class II derived from? What are they recognised by?
-Derived from proteins of extracellular pathogens that are endocytosed by antigen presenting cells.
-Recognised by Helper T cells
What happens in the MHC class I pathway?
- Proteins in cytosol are broken down into peptides by proteosomes
- Peptides are transported into the endoplasmic reticulum by the TAP transporter
- In this compartment, some peptides bind to newly synthesised MHC class I proteins & the peptide-MHC complexes are transported to the cell surface in membrane vesicles
- At the cell surface, the peptide-MHC complex may be recognised by CD8 expressing CTLs that recognise that the peptide is pathogen-derived & kill the infected cell to eliminate the pathogen
What are some examples of antigen presenting cells (APCs)?
Dendritic cells, macrophages, B cells
What happens in the MHC class II pathway?
1.Antigens processed in class II pathway are derived from the extracellular environment & are endocytosed in membrane vesicles
2.The endocytic vesicles fused with lysosymes contain various cellular proteases that break the protein into peptides (these are generally bit longer than the ones produced by class I pathway)
3.The endolysosomal vesicles fuse with membrane vesicles that contain newly synthesised MHC class II proteins
4.MHC class II complexes with extracellular peptides are transported to surface of APC where they may be recognised by antigen-specific helper T cell
What are the MHC class II proteins synthesised together with, and what happens to this during the pathway?
1.The class II proteins are synthesised together with a protein called the invariant chain.
2.which blocks the antigen binding site of the MHC class II molecules so that it can’t be occupied by peptides from intracellular proteins.
3.But when the class II-containing vesicle fuses with the endolysosomal vesicle, proteases now digest the invariant chain so that the peptide binding site becomes available for binding to peptides derived from extracellular proteins
What does it mean to say MHC peptide binding is highly promiscuous?
Individual MHC molecules must be able to bind to an enormous number of different peptides so as to alert the immune system to a large range of different pathogens- promiscuous binding
- Few residues in peptide critical for binding.
- MHC I binds peptides of 8-10 residues, only 1 or 2 contribute to binding.
3.MHC II binds peptides 12-17 residues, only 2 or 3 contribute to binding.
- All other positions can vary so very large number of peptides can bind to any MHC molecule.
5.In this example, 16 amino acid peptide, 3 positions (yellow) required to bind MHC.
What do some of the smaller populations of T cells have?
They express γẟ (gamma delta) T cell receptors, which can recognise other antigens such as pathogen-derived metabolites & lipids
These antigens don’t require processing & is displayed on the target cell bound to MHC class I-like molecules that are expressed from entirely separate gene loci
What are naive T cells?
Resting T cells that have not previously encountered antigens before
What are naive T cells activated by and where does it occur?
Specialised antigen presenting cells (APCs): dendritic cells (DC), macrophages
APC’s express both MHC class I and MHC class II proteins, so bind to and activate both CD4 Th and CD8 Tc lymphocytes
Activation occurs in lymph nodes
What 3 signals are needed for Th cell activation?
- T cell receptor recognises MHC class I or II with the loaded antigen. CD3 is recruited to the TCR and can be phosphorylated and transmit the signal.
- Signal given by co-stimulatory proteins, expresses 2 CD28 on the T cell. This is important to strengthen the first signal given by the TCR, the first signal alone is not enough as the T cell will become anergic.
- Signal given by cytokines secreted (IL-2) by the antigen presenting cell. These cytokines determine what type of immune response is going to be produced.
The T cell is now activated
What can activated Th cells proliferate and give rise to?
T effector cells
T memory cells
Induction of what expression on Th cells is needed for the cell to become fully activated and produce t effector cells and t memory cells?
CD40
CD40L
What signals are involved in cytotoxic T cell activation?
Tc activation is complex:
- MHC-I:antigen TCR, CD3
- Co-stimulatory proteins, CD80/CD86 CD28
- Requires Th activity:
production of IL-2
stimulation via APC derived inflammatory cytokines such as IL-12 - Activated CTL proliferate: effector and memory
slide 25
What do cytokines released from APC determine?
Th1:
IL-12 and IFN-a are released from the APC and acts on the Th1 cell.
Th1 cells releases IL-2,IFN-y
Activation of macrophages, NK cells, CD8 CTL
Targeting intracellular viruses and bacteria.
Th2:
IL-4 is released from the APC and act on the Th2 cell.
Th2 cells releases IL-4 and IL-5
Activation and recruitment of eosinophils, basophils and mast cells
Targeting extracellular parasites
Th17:
IL-6 and TGF-b are released from the APC and act on the Th17 cell.
Th17 cells releases IL-17 and IL-22
Activation and recruitment of neutrophils, macrophages, antimicrobial peptides and ROS.
Targets Extracellular bacteria, fungi
How and why is the immune response switched off?
-Inhibitory receptors = CTLA-4, LAG3 = replace activatory signals
-Express apoptotic receptors = FAS
- leads to reduction of immune cells as they’ve proliferated massively upon activation but once the pathogen is no longer there, we do not need so many immune cells anymore.
- The few cells that remain = memory cells
What does each T cell have an antigen receptor of?
Unique specificity
How is diversity of a T cell receptor generated?
ALPHA CHAIN: One of each region (variable and joining) has to be brought together to form an exon that encodes the function and complete variable antigen binding domain.
Requires rearrangement of chromosome at this locus mediated by RAG 1 and 2.
Looping off DNA randomly aligns one of the v and j segments
Addition or elimination of nucleotides increases diversity further.
Same for Beta but BETA needs the recombination of V,D and J.
Any beta chain can joint with any alpha chain, increasing diversity further.
How does recombination & nucleotide addition affect diversity?
slide 32
What happens after T cells mature in the thymus?
They undergo positive and then negative selection.
The purpose of selection is to retain only T and B cells that recognise foreign antigens but not self antigens (or they will attack the body’s own tissues)
What do immature T cells express?
TCR as well as CD4 and CD8 (double positive, DP)
What happens to T cells that don’t bind self to MHC, that bind to MHC class II & those that bind to MHC class I?
T cells that do not bind self MHC undergo apoptosis
T cells that bind to self MHC II (on epithelial cells or dendritic cells) in thymus cortex become CD4 single positive (SP) cells
T cells that bind to MHC I become CD8 SP cells
This is positive selection of T cells in the thymus
What is negative selection of T cells in the thymus?
The T cells that survived positive selection now have to go through negative selection:
Surviving SP T cells migrate to medulla
SP T cells that bind weakly/moderately to self antigens associated with MHC, survive
SP T cells that bind strongly to self antigens/MHC undergo apoptosis or become Treg cells
What are the sequence of events during selection?
- Thymocytes express CD4 and CD8 becoming double positive cells.
- Double positive cells bind to MHC I or MHC II
- Cells become CD4 single positive or CD8 single positive
- Double positive cells in the Cortex which do not bind MHC undergo apoptosis.
What is peripheral tolerance?
Peripheral tolerance mechanisms are crucial for preventing autoimmune reactions, where the immune system attacks its own cells and tissues.
What are the 2 key mechanisms of peripheral tolerance?
Regulatory T cells (Tregs) : Suppress activity of other immune cells e.g self reactive T and B cells, preventing harmful immune responses against body’s own tissues.
Anergy: Immune cells become inactive when they encounter self-antigens without proper signals, reducing damage to healthy tissues.
