Immunology 6- T lymphocytes Flashcards
Describe T lymphocytes
detects and combats intracellular pathogens
“sees” foreign antigen via a receptor on its cell surface (T cell receptor; TCR)
antigen seen is a small peptide fragment of the pathogen; peptide presented by MHC molecule on the surface of a host infected cell (i.e. self MHC + foreign peptide)
Why do we need T cells
Antibodies can’t get inside cells, hence we need T cells to combat intracellular pathogens
Describe the TCR
The TCR resembles a membrane-bound form of antibody Fab fragment in structure, that is it consists of two polypeptide chains each containing a variable domain and a constant domain. There is a very large number of different TCRs present in each individual, providing a large T cell repertoire.
Describe the structure of the TCR
The TCR is a heterodimeric membrane protein. The two types of receptor are those with alpha-beta chains, present on approximately 95% of T lymphocytes, and those with gamma-delta chains, found on approximately 5% of T lymphocytes. The two chains have roughly equal molecular masses. The TCR domains farthest away from the membrane are analogous to the Ig variable domain. The domains closer are analogous to the Ig constant domain. Antigen binds to a site created by the V domains of the TCR. The two chains are linked by disulphide bonds. A cytoplasmic tail is present on both chains.
What has the 3-D structure of the TCR revealed
The existence of 3 hypervariable regions in the variable region.
These hypervariable regions are relatively flat that contacts residues of both the MHC and the peptide antigen.
What is the charge of the amino acid residues in the transmembrane region
Positive
What do all T cells express
CD3 polypeptides
Describe the key differences between alpha-beta TCRs and gamma-delta TCRs
Gamma-delta TCRs can recognise lipid molecules as well as peptides, they also do not always recognise MHC and are not MHC restricted.
Describe how the TCR associates with the CD3
The positive charge of the TM region of the TCR associates with CD3 polypeptides and delivers signals to the TCR, the residues become tyrosine kinase.
Describe how a T cell sees the antigen
2 major populations of T cells Use CD4 co-receptor, see peptide on MHC class II - “class II restricted” Use CD8 co-receptor, see peptide on MHC class I - “class I restricted” Co-receptor molecules bind to the relevant MHC (conserved part, not the antigenic peptide), increase the avidity of T cell-target cell interaction and are important in signalling
What is meant by a processed antigen
They are small peptide fragments derived from larger proteins (some specialised T cells are able to recognise non-peptide antigens).
Describe the differences in function of CD8 and CD4 T cells
CD8 (Tc or CTL): most are cytotoxic and kill target cells - also secrete cytokines (Interferon-gamma)
Induce apoptosis in the target cell (programmed cell death, suicide)
CD4 (T helper cells, Th): secrete cytokines
Recruit effector cells of innate immunity, help activate macrophages
Amplify and help Tc and B cell responses
What can CD4 populations be divided into
Th1, Th2 or Th17 depending on the cytokines that they release.
Where do T lymphocytes develop
T lymphocytes develop in the thymus from bone marrow derived precursors.
Describe the development of T lymphocytes in the thymus
Upon migrating to the thymus and locating in the subcapsular zone, bone-marrow derived thymocytes do not express CD4 or CD8, this is known as the double negative stage. At this stage the TCR genes are in their germline (unrearranged) configuration. In the cortex, gene rearrangement of the TCR gene occurs, and an important choice made at this stage is commitment to alpha beta lineage or delta gamma lineage. In the alpha beta lineage, a preTCR is formed consisting of a beta chain and a surrogate alpha chain. The next major step is the double-positive stage, where the cells express both CD4 and CD8. These cells then undergo selection for a useful TCR, positive selection allows the survival of TCRs that recognise MHC, but not too strongly. In the thymic medulla, negative selection occurs where T cells that recognise self MHC with high affinity are deleted. Lineage commitment then occurs, where MHC becomes single positive depending on which MHC class they recognise.
Describe the differences between gene rearrangement in the beta and alpha chains
Beta- 2 recombination events, alpha 1
Beta chains had a Diversity segment as well as a V, J and C segment
Beta has two constant regions
How many different alpha beta TCRs can be generated
10^10 different abTCR’s may be created by gene rearrangements
Describe the first selection checkpoint
Pre TCR checkpoint:
Is the new b chain functional?
Yes: Survival and development
to CD4+CD8+ ab TCR+
No: Death by
apoptosis
Describe the second selection checkpoint
Is the ab TCR functional? (binds MHC weakly)
Is the ab TCR dangerous/autoreactive?
ONLY 5% OF THYMOCYTES SURVIVE SELECTION
Describe the major histocompatibility complex
MHC molecules display a sample of the internal contents of cells at the cell surface for possible immune cell recognition
MHC molecules are markers of “self”, and indicate the “health” of cells
MHC molecules continuously present peptides, even in the absence of infection
Explain how the MHC gets to the cell surface
MHC needs a peptide to get to the cell surface, hence in the absence of disease, a self peptide will be expressed. MHC cannot distinguish between self and viral peptides, discrimination is by TCR.
What did skin transplantations between strains of mice show
Transplantation of skin between strains showed that
rejection or acceptance was dependent upon
the genetics of each strain
Describe class 1 and class 2 MHC
transplantation antigens: MHC class I also found a second class of gene mapping to the same locus: controls ability to mount an antibody response (regulatory) originally called immune response genes: now MHC class II Nearly all cells express MHC 1 ( to varying levels), MHC 2 are normally expressed by 'professional' APC (dendritic, macrophages and B lymphocytes).
Describe the genetic basis of MHC
the MHC is a group of tightly linked genes important in specific immune responses
found in all vertebrates
MHC molecules present antigens to T lymphocytes
Found on chromosome 6, referred to as the HLA.
