Intro to T cells and TCR Flashcards
How do T cells and TCRs function?
Must be able to recognise some feature of the pathogen from outside the infected cell
- This can’t be done by antibodies since they recognise intact proteins
achieved by a complex process of antigen proteolysis (processing) inside the infected cell
Peptides are presented on the cell surface by MHC class I/ II molecules
MHC-peptide combination is recognised by the T cell receptor (TCR)
the repertoire of possible TCR specificities is huge
Recognition activates signalling processes inside the T cell leading to functional responses
T cells can be either short-lived “effector” cells or they can become “memory cells”
What is the Listeria model for t cells?
T cells essential for cell-mediated immunity
Listeria model (an intracellular bacteria) ( lives inside macrophages)
- Adoptive transfer experiments, transferring serum with antibodies
- Activated macrophages allow high killing of listeria but without it, killing is low
- T cell itself is not always effector, implies that T cells work with something else - macrophages
What is the Listeria model for t cells?
T cells essential for cell-mediated immunity
Listeria model (an intracellular bacteria) ( lives inside macrophages)
- Adoptive transfer experiments, transferring serum with antibodies
- Activated macrophages allow high killing of listeria but without it, killing is low
- T cell itself is not always effector, implies that T cells work with something else - macrophages
The requirement for T cells is pathogen specific
Killing of listeria and some other intracellular bacteria requires T cells and macrophages
Killing of parasites by T cells requires IgE and eosinophils and/or mast cells
Killing of many virally-infected cells by T cells does not require any other cell types – direct effectors
several types of t cells
- cytotoxic t cell
- helper t cells - CD4
- suppressor T cells - maintain tolerance
What is MHC restriction?
MHC restriction: T cells have to recognise both peptide and the MHC allele presenting it
Will only recognise antigen if it is presented by self MHC
If presented by wrong MHC – no recognition
If right MHC but wrong peptide – no recognition
What occurs without dual antigen/MHC recognition?
Toxic shock syndrome e.g. caused by the staphylococcal syndrome toxin-1 which acts as a superantigen
- Doesn’t care what the peptide is, causes massive immune reaction that is non-specific
The superantigen binds directly to both MHC class II and T cell receptor, triggering multiple T cells to produce cytokines
What is the TCR structure?
TCR only has two chains instead of four
Only one binding site
Heterodimer, a and beta chain
Constant and variable region
Doesn’t have long c terminus and is embedded in membrane, no free TCR
Cytoplasmic tail to signal with other molecules
Differences between TCR and Ig structure
Both have highly variable antigen-binding domains attached to constant regions
differences:
- Antibodies can have multiple binding sites; TCR has one
- TCRs do not bind to native antigens but only to processed (cleaved) peptides (7-20 amino acids) bound in the cleft of MHC-encoded proteins whilst antibodies recognise whole antigen.
- Unlike antibodies, the TCR is not a direct effector
what does rearrangement of TCR genes generate?
Generates diversity as for immunoglobulins
No complete gene exists in the germline
As for Igs, TCR genes are encoded in separate segments (Vs, Js and a C for TCRa and Vs Js Ds and Cs for TCRB)
TCR genes are rearranged during t-lymphocyte development in the thymus
Insertion of non-coded bases and variation in exact joining site is more important in TCRs than in Igs
Results in diverse amino acid sequences in the CDR-3 loops, most of which makes contact with the presented peptide
Origins of t cells
Derive from haematopoietic stem cells in bone marrow
Emigrate to the thymus (thymus-dependent lymphocytes = T cells) in thymus
Acquire their TCR in the thymus and become CD4+ or CD8+ cells - CD8 effector, CD4 helper
Naïve T cells migrate to secondary lymphoid tissue (lymph nodes)
Naïve T cells interact with peptides presented on MHC molecules by antigen presenting cells (APCs)
Productive interaction with a T cell expressing a high affinity TCR leads to clonal selection and amplification of the T cell
Selected and amplified cells leave lymph nodes and target infected tissues
selection of the t cell repertoire
T cell repertoire is selected in the thymus during development
Travel from bone marrow to thymus to develop
Adults have atrophied thymus , has different sites so is specialised.
Newly arrived cells in the thymus are CD4−CD8− cells, and are termed early thymic progenitor (ETP) cells; they do not express the TCR genes.
- CD4- and CD8- they are called DOUBLE NEGATIVE cells
In thymus these cells upregulate CD25 (the IL2 receptor) and the recombination genes RAG1 and RAG2 and they re-arrange the TCRβ locus first (not TCRa)
Having rearranged the TCRβ gene the cells then “try it out”!
T cells express an invariant α-chain, pre-Tα alongside the TCRβ gene
If the rearranged β-chain successfully pairs with the invariant α-chain, signals are produced which cease rearrangement of the β-chain (and silences the alternate allele)
If pre-TCR forms, these cells undergo a round of proliferation and then begin to re-arrange the TCRα locus
Concomitant with this, production of a pre-TCR signals cells to start to transcribe the genes for CD4 and CD8. BOTH genes are stimulated, leading to the production of CD4+CD8+
DOUBLE POSITIVE cells and express single specific TCR
TCR rearrangement process is random and generates millions of different receptor specificities
TCR positive, CD4+/CD8+ Double-positive thymocytes migrate deep into the thymic cortex, where they are presented with self-antigens.
self-antigens are expressed by thymic cortical epithelial cells (CTECs) on MHC molecules on the cell surface.
Only thymocytes that interact with MHC-I or MHC-II will receive a vital “survival signal”. cTECs are unusual in expressing both MHC class I and MHC class II genes
For alpha beta T cells, the TCR is first expressed during development in the thymus (so this is where selection occurs)
T cells undergo “negative selection” eliminating self-reactive cells
T cells undergo “positive selection” of cells with TCRs capable of interacting with self-MHC
What happens to cells that do not interact strongly enough with MHC peptide complexes?
cells that don’t interact will die, death by neglect” (no survival signal). - cells with low affinity selected against
Process ensures that the selected T cells will have an MHC affinity that can serve useful functions in the body (i.e., the cells must be able to interact with MHC and peptide complexes to effect immune responses).
Vast majority of developing thymocytes will die during this process.
thymocyte’s fate is determined during positive selection. Double-positive cells (CD4+/CD8+) that interact well with MHC class II molecules will eventually become CD4+ cells, whereas thymocytes that interact well with MHC class I molecules mature into CD8+ cells.
T cell becomes a CD4+ cell by down-regulating expression of its CD8 cell surface receptors.
If the cell does not lose its signal, it will continue downregulating CD8 and become a CD4+, single positive cell
How are potentially autoimmune cells removed?
Negative selection removes thymocytes that are capable of strongly binding with “self” MHC peptides.
Thymocytes that survive positive selection migrate towards the boundary of the cortex and medulla in the thymus. While in the medulla, they are again presented with a self-antigen presented on the MHC complex of medullary thymic epithelial cells (mTECs).
Thymocytes that interact too strongly with the self-antigen receive an apoptotic signal that leads to cell death.
However, some of these cells are selected to become Treg cells.
The remaining cells exit the thymus as mature naïve T cells.
process is an important component of central tolerance and serves to prevent the formation of self-reactive T cells that are capable of inducing autoimmune diseases in the host.
What are the two important features of thymic selection
The problem is solved by mTECs expressing a transcription factor called AIRE, which allows promiscuous expression of self-antigens from all tissues of the body on MHC class I – making peptides from rare proteins expressed in specific tissues – this eliminates T cells that recognise differentiated tissues – this allows high affinity TCR to be produced
This leaves the problem of how you negatively select T cells that strongly recognise self-antigens presented on MHC class II.
This is solved by thymic dendritic cells which can phagocytose mTECs; this allows for presentation of self-antigens on MHC class II molecules
