An introduction to T cells and the T cell receptor Flashcards
Describe the recognition process by T-cells
Must be able to recognise some feature of the pathogen from outside the infected cell!
- This obviously can’t be done by antibodies since they recognise intact proteins
* It is achieved by a complex process of antigen proteolysis (processing) inside the infected cell
- Peptides are presented on the cell surface by MHC class I or class II molecules
* The MHC-peptide combination is recognised by the T cell receptor (TCR)
- Just like antibodies, 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 type of immunity are T-cells?
- Essential for cell-mediated immunity
- The Listeria model (an intracellular bacteria)
How do T-cells activate macrophages?
How is the requirement for T-cells pathogen-specific?
- The nature of the cell-mediated immune response
depends upon the pathogen - Killing of listeria and some other intracellular
bacteria require 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
What are the several different types of T-cells?
List their main functions and the pathogens they target.
Describe MHC restriction
cells have to recognise both peptide and the MHC allele presenting it
Will only recognise antigen if it is presented by self MHC
What would happen without the need for
dual antigen/MHC recognition?
- Toxic shock syndrome e.g. caused by the staphylococcal syndrome toxin-1 which acts as a superantigen
- The superantigen binds directly to both MHC class II and T-cell receptor, triggering multiple T cells to produce cytokines
Describe the T-cell receptor (TCR)
- T cells all possess receptors which, like surface
immunoglobulins (the antigen receptors on B-cells), have a very large range of specificities - Like Ig, this is due to highly variable amino acid sequence of the variable (antigen-binding) region
Describe the anatomy of the thymus
What are the similarities and differences between the T-cell receptor structure and immunoglobulin structure?
- Highly variable antigen-binding domains attached to constant regions
- Clearly they share a common evolutionary origin
- BUT - there are important 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.
*, Unlike antibodies, the TCR is not a direct effector
What determines TCR diversity?
Rearrangement of TCR genes 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 TCRalpha and Vs Js, Ds and Cs for TCRBeta).
Where are TCR genes rearrangement?
What does it require?
TCR genes are rearranged during T-
lymphocyte development in the thymus
- Gene rearrangement is essentially as for
immunoglobulin genes, requiring RAG genes and signalling sequences at the appropriate sites to allow the looping out or inversion of intervening DNA to bring single V, D, J and C’s together
Describe how junctional diversity is prominent in TCR genes
- Insertion of non-coded bases and variation in exact joining site is more important in TCRs than in Igs.
- This results in diverse amino acid sequences in the CDR-3 loops (α green; β magenta), most of which make contact with the presented peptide
Where do T-cells originate?
Describe their maturation
- Derive from haematopoietic stem cells in bone marrow
- Emigrate to the thymus (thymus-dependent lymphocytes = T cells)
- Acquire their TCR in the thymus and become CD4+ or CD8+ cells
- 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
Where is the selection of the T-cell receptor?
The T cell repertoire is selected in the thymus during development
What happens to CD4−CD8− cells when they first enter the thymus?
- The 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. As a result of being CD4- and CD8- they are called DOUBLE NEGATIVE cells
- In the thymus these cells upregulate CD25 (the IL2 receptor) and the recombination genes RAG1 and RAG2 and they re-arrange the TCRβ locus
What happens to the CD4−CD8− cells after having rearranged the TCRβ?
- Having rearranged the TCRβ gene the cells then “try it out”!
- The T cells express an invariant α-chain called pre-Tα alongside the TCRβ gene
- If the rearranged β-chain successfully pairs with the invariant α-chain, signals are produced which cease the rearrangement of the β-chain (and silence the alternate allele)
- If the pre-TCR forms, these cells undergo a round of proliferation and then begin to re-arrange the TCRα locus
- Concomitant with this, the 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
T cell receptors produced can be grouped into 3 classes:
- Potentially useful in interacting with foreign pathogens (want these)
- Pretty useless in that they don’t interact with anything
- Potentially actually harmful - reacting with self-antigens ( you don’t want the latter two)
How do TCR-positive, CD4+/CD8+ Double-positive thymocytes receive survival signals?
-They migrate deep into the thymic cortex, where they are presented with self-antigens.
-These self-antigens are expressed by thymic cortical epithelial cells (CTECs) on MHC molecules on the cell surface.
-Only those 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
Describe the Selection of the T cell repertoire for alpha beta T-cells
- For ab 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
Describe positive selection for cells that do not interact strongly with MHC
Cells that do not interact strongly enough with MHC peptide complexes will die by “death by neglect” (no survival signal).
This 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).
The vast majority of developing thymocytes will die during this process. The process of positive selection takes a number of days
Describe positive selection for those that interact well with MHC I and MHC II
- A 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.
- A T-cell becomes a CD4+ cell by down-regulating the 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.
What happens to thymocytes that may cause autoimmunity?
Positive selection does not remove thymocytes that may cause autoimmunity. The potentially autoimmune cells are removed by the process of negative selection, which occurs in the
thymic medulla
Describe negative selection
- 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. This 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.
