Generation of Diversity in The T Cell Repertoire Flashcards
Antigen – define
Antigen – A combination of ‘antibody’ and ‘generate’.
Any molecule that can bind specifically to an
antibody
Proteins,
carbohydrates and lipids capable of binding to B-cell receptors, T-cell
receptors and/or innate immune receptors
Explain the immune reactions to epitopes
• Adaptive immune reactions occur to specific epitopes (portions of the antigen)
as opposed to the entire antigen itself
Infection and vaccination usually induce what
Infection and vaccination usually induce polyclonal T- and B-cell responses
Which immune cells recognise and process antigen? - list
MONOCYTES MACROPHAGES
DENDRITIC CELLS
B-CELLS
“Professional” Antigen-Presenting Cells (APCs): - define
“Professional” Antigen-Presenting Cells (APCs): Immune cells that express
high levels of surface MHC Class II and can efficiently induce T-cell responses
• Highly phagocytic cells - which ones and their effect
Macrophages + DC
Highly phagocytic cells – induce strong T-cell responses and inflammation.
Important for protection against Mycobacterium tuberculosis
Compare specific functions of macrophages vs dendritic cells
• Macrophages better-equipped to kill pathogens (higher NO production); DCs
better at migrating to lymph nodes (via CCR7) and presenting antigen to Tcells
B-CELLS - distribution
• Highly abundant in blood and mucosal tissues
Macrophages + DC - distribution
• Rare in peripheral blood - enriched in mucosal tissues
B-CELLS - functions
Receptor-mediated internalisation of antigens, as opposed to phagocytosis
• Primary function to make antibody (plasma cell) – but still very good at antigen
presentation
• Possibly main inducer of T-cell immune response to pathogens such as
Neisseria meningitidis
Endogenous antigen processing - describe
UPTAKE
Antigens/pathogens already present in cell
DEGRADATION
Antigens synthesised in the cytoplasm undergo limited
proteolytic degradation in the cytoplasm
ANTIGEN-MHC COMPLEX FORMATION Loading of peptide antigens onto MHC class I molecules is different to the loading of MHC class II molecules
PRESENTATION
Transport and expression of antigen-MHC complexes on
the surface of cells for recognition by T cells
Macrophages function
Macrophages have welldeveloped lysosomal systems
• Specialised for motility,
phagocytosis and the introduction
of particles to the lysosomal system
Is exogenous antigen processing sufficient?
Most cell types do not have lysosomal systems
developed as well as macrophages
BUT
Viruses can infect most cell types
A non-lysosomal mechanism to process antigens for presentation to T cells is required
Non-lysosomal antigen processing - list types
ANTIGENS FROM INACTIVE VIRUSES ARE PROCESSED VIA THE EXOGENOUS PATHWAY
ANTIGENS FROM INFECTIOUS VIRUSES ARE PROCESSED VIA THE
ENDOGENOUS PATHWAY
Immune response for inactive virus vs infectious virus
Inactive virus raises a weak CTL response
The processing of antigens from inactive viruses is sensitive to
lysosomotrophic drugs
I fectious virus raises a strong CTL response
The processing of antigens from infectious viruses is NOT sensitive to
lysosomotrophic drugs
Most CTL recognise antigens generated via a non-lysosomal pathway
Requirements for non-lysosomal antigen processing
Protein synthesis is required for non-lysosomal antigen processing
Exogenous pathogens eliminated by
Antibodies and phagocyte activation by T helper cells that use antigens generated by exogenous processing
Endogenous pathogens eliminated by
Killing of infected cells by CTL that use antigens generated by endogenous processing
MHC class I - describe:
- Expressed where
- Binds what
- Presents to
- Antigens from
Expressed on
all nucleated
cells
Binds short
peptides (8-10
amino acids)
Presents to
CD8+ T-cells
Antigens from
the cytosol (+
crosspresentation)
MHC class II - describe:
- Expressed where
- Binds what
- Presents to
- Antigens from
Expressed on
APCs and
activated T-cells
Long peptides
(typically 15-24
amino acids)
Presents to
CD4+ T-cells
Antigens from
phagosomes
and ensodomes
The T-cell receptor - binds what
Binds to peptide-MHC
(pMHC) complexes –
cannot recognise peptide
alone
The T-cell receptor - diversity and structure
Huge diversity – potentially
up to 1 x 1013 different TCRs
Exists in a TCR complex
with accessory molecules
such as CD3
T cell receptor and B cell receptor - Similarities to B cell receptor/antibody:
Similarities to B cell receptor/antibody: • Belongs to Ig superfamily • Like Fab fragment of antibody • Large diversity • Single specificity
T cell receptor and B cell receptor - Differences to B cell receptor/antibody:
• Lower affinity • Cannot be released • No Fc fragment, so no cellular functions • Single rather than two binding sites • B cell receptor/Ab: 5 classes • T cell receptor: 2 classes (ab and gd)
Mechanisms which generate B-cell receptor diversity (before/after AT stim)
Mechanisms which generate B-cell receptor diversity
Before antigen stimulation: Somatic recombination
After antigen stimulation: Somatic hypermutation
Mechanisms which generate T-cell receptor diversity
before/after AT stim
Mechanisms which generate T-cell receptor diversity
Before antigen stimulation: Somatic recombination
After antigen stimulation: None
T cell receptor diversity - Receptor gene rearrangement takes place during
Receptor gene rearrangement takes place during T-cell
development in thymus
Three signal model of T-cell activation - list + compare them
- Peptide-MHC (pMHC) →
- Co-stimulation →
- Cytokines →
Signals 1 + 2 alone will activate a naïve T-cell, but Signal 3 is also
important for a strong response and also determining T-cell phenotype
APC-T-cell interactions - describe signal one
The main signal (Signal One) is delivered from the APC by a
peptide-MHC complex to the TCR
APC-T-cell interactions - describe signal two
The co-stimulatory signal (Signal Two) is delivered from the
APC by germline-encoded accessory receptors such as the ‘B7
family’ (CD80 and CD86) – although many of these receptors
are not fully characterised or understood
APC-T-cell interactions - describe signal three
Lastly, Signal Three is formed of cytokines secreted by the APC to determine the T-cell phenotype. • IL-12 promotes TH1 cells • IL-4 promotes TH2 cells • IL-23 promotes TH17 cells
The immunological synapse - define
Complex interaction of many molecules – but simplistically Signals 1 and 2
are central, and surrounding integrins and accessory molecules help to
stabilise the interaction
Negative regulators of antigen presentation provide
Negative regulators of antigen presentation provide an ‘immune
checkpoint’ to limit T-cell activation→HOMEOSTASIS
Negative regulators of antigen presentation - important molecules
Two important molecules – CTLA4 (Cytotoxic T-Lymphocyte-Associated
Protein 4) and PD-L1 (Programmed Death-Ligand 1) are crucial for
dampening the T-cell response
T-cells - explain positive selection
• T-cells arise from the thymus, which is a ‘school’ for T-cells.
T-cells are exposed to self-antigens and tested for reactivity
T-cells that can’t bind self antigen-MHC are deleted →
POSITIVE SELECTION
• These T-cells are useless because they won’t protect
against pathogens
T-cells - explain negative selection
T-cells that bind self antigen-MHC too strongly are also
deleted → NEGATIVE SELECTION
• These T-cells are dangerous because they are too selfreactive
the ‘master
controller’ of Regulatory T-cells (TREG) - define
In some models (STOCHASTIC MODEL), a proportion of Tcells that are strongly reactive to self-antigen will express
the transcription factor FOXP3, which is the ‘master
controller’ of Regulatory T-cells (TREG)
the ‘master
controller’ of Regulatory T-cells (TREG) - function
Thymically-derived TREG that are reactive
for self-antigen can compete with any
autoreactive T-cells and secrete antiinflammatory cytokines
IMMUNE EVASION - describe
Many organisms depend on human host for survival (‘obligate parasites’) –
need to co-exist with the host immune system → IMMUNE EVASION
Mycobacterium tuberculosis - effects on immune system
• Up-regulates PD-L1 on APCs
to shut down T-cell activation
• Blocks MHC Class II expression via multiple
mechanisms
Neisseria meningitidis - effects on immune system
• Blocks DC activation –
low CD40, CD86 and MHC Class I & II
expression
• Antigens (capsule) with homology to selfantigen, therefore anergic T-cells
Neisseria gonorrhoeae - effects on immune system
Expresses Opa protein, which binds to T-cells
and induces tyrosine phosphatases that ‘switch
off’ key molecules involved in TCR signalling
HIV - effects on immune system
• Up-regulates PD-1 on T-cells,
which antagonises TCR signalling
• Binds to DC-SIGN to suppress DC activation
via Rho-GTPases
Herpes Simplex Virus (HSV) - effects on immune system
• Herpes Simplex Virus (HSV)
• Produce protein which binds to and
inhibits TAP
• Prevents viral peptide transfer to ER
Adenovirus - effects on immune system
Adenovirus • Produce protein which binds MHC class I molecule • Prevents MHC class I molecule from leaving ER
