T cells Structure and Rearrangement Flashcards
What are T cells?
T lymphocytes are a type of immunological cells that can be distinguished with TCRs on their cell surface. There are two different types of TCRs
1. aB - heterodimer of 2 disulphide-linked polypeptides
- gD - structuarally similar but with different polypeptides
Both of these receptors are associated with the CD3 complex – set of 5 polypeptoides – together they make the TCR-CD3 complex
Approx 90-95% of serum human T cells are aB and the remaining are gD
What are the stages of development of T cells?
- T cells start off as pluripotent stem cells in bone marrow (common progenitor)
- They emigrate to Thymus (thymus-dependent lymphocytes = T cells), the primary lymphoid organ (concerned with lymphocyte production) where they mature via differentiation, proliferation and selection – rearrange their TCR
- In the thymus, T cells aquire their specific antigen receptors (TCRs) to deal with antigenic challenges, cells with autoantigen rececptors are eliminated and T cells will learn how to recognise appropirtiate self MHC molecules
- They then exit into the circulation as naïve T cells then when they meet their first antigen, they become effector T cells
- Patients with complete DiGeorge’s syndrome lack thymus and therefore T cells
What is the thymus and what happens here?
The thymus is a bilobed organ in the thoracic cavity overlying the heart and major blood vessels. Within each lobule there is:
- Outer tightly packed cortex which contains most of the immature proliferating thymocytes (lymphoid cells)
o Inner cortex
o Outer cortex
- Inner medulla containing more mature cells
o Contains the high endothelial venule (HEV) – this is where PreT cells come from the foetal love or bone marrow and where the cycle of development starts
- The cycle starts when the pre-T cells enter the thymus from the bone marrow via the HEV
- They migrate to the inner cortex and are now Double negatibve (DN) 1 cells which are CD44+ for CD4 and CD8 expression
- DN1s move towards th outer cortex and differentiate into DN2 (CD44 and CD25) and DN3 (low conc. of CD44 and CD25)
- These thymocytes accumulate in the subcapsular region where they actively differentiate into Double positive (DP) cells (CD4+ AND CD8+)
- Thymocytes then reverse their polarity and move back towards the medulla. They are then selected and become Single Positive cells (SP) (CD4+ OR CD8+)
- They will then leave the thymus via the HEVs, heading for secondary lymphoid tissue
Describe positive and negative selection
Positive selection – ensures only the TCRs with an intermediate affinity for self-MHC develop further
- There is evidence that this is mediated via TECs (cortical thymic epithelial cells) acting as APCs
- T cells with either very high or very low self MHC affinities undego apoptosis in the cortex (at DP stage)
- Intermediate affinity T cells survive and carry on to next stage of selection
Negative selection: ensures that only t cells that fail to recognise self antigen continue developing
- Occurs in the deeper cortex, corticomedullary junctionand in the medulla
- The cells which recognise self antigen go through apoptosis
- Cells then differentiate to SP cells and leave the thymus to the peripheral/secondary lymphoid areas
What is the biggest difference in what B cells and T cells recognise?
The biggest difference between B cells and T cells is that T cells do not recognise native antigens.
How does T cell development generate diversity?
For each chain (aB or gD) there is a variable region and a constant region. The variable region is the antigen-recognising part
TCRs have CDRs with the most highly variable one, CDR3, whose diversity is generated via V(D)J recombination. this Generates the levels of diversity – needs to be rearranged
Recombination mechanism is the same as B cells but T cells don’t require somatic hypermutation or class switching as there is no secreted form of TCR. Rearrangement occurs in the B chain first in the DN stages of development in the thymus
Yhe 12/23 rule applies here and additional nucleotides are added by TdT between the gene segments.
What is the CD3 complex ?
The TCR assembles with other proteins to form a signalling complex. It assembles with the CD3 polypeptide which is put together in the endoplasmic reticulum
It consists of four invariant chains – gamma, delta, epsilon and zeta, which are arranged as heterodimers of gE and DE
The zeta chain is separate and is mostly intracellular, made up of
o Small extracellular domain
o A transmembrane domain with negative charge
o A large cytoplasmic tail with ITAM
All chains have ITAMs (mmuno-receptor Tyrosine-based Activation Motif ) attached . These allow the receptor to transmit signals into the cell following activation and allow for MHC attachment
Where do mature T cells go after they exit the thymus?
Mature T cells in circulation are known as naïve T cells until they encounter their first antigen via APCs in secondary lymphoid tissue such as lymph nodes, spleen or GALT (gut-associated lymphoid tissue)
Following encounter and proliferation, exit as ‘effector’ T cells – ready to do something in periphery when antigen has been detected.
What are effector T cells
Effector T cells are a group of cells that actively respond to a stimulus e.g. costimulation. These include CD4+, CD8+ and T Regulaotry cells (Treg)
Effector cells will redistribute to sites of infection when signalled by chemokines and newly expressed adhesion molecules
What are adhesion proteins and how do they help signal the effector t cell to site of infection?
When effector proteins want to redistribute to the site of infection they stop producing L-selectin (protein that hones to the lymph nodes). They the start expressing VLA-4 adhesion proteins which recognise VCAM-1 target on vascular endothelium during inflammation due to infection
The T cells will constantly be be patrolling and checking cells for foreign antigens. Non specific adhesion allows for initial binding on potential targets. If they don’t find the specific antigen then they will move off the target.
If the correct antigen is found, there is MHC/T cell signalling inducting a conformational change and a direct target release of effector molecules particularly for CD8 cytotoxic cells
What are the main types of T cells?
- Helper T cells - TH1 and TH2
- TH17
- T Follicular Helper cells
- Cytotoxic T cells (CD8)
What his the main function of T helper cells (CD4) ?
- Activate and ‘help’ other cell types to co-ordinate immune response
- Achieved through expression of cell surface proteins and soluble cytokines
- Acquired Immune Deficiency syndrome (AIDS) results from loss of Helper T cells following HIV infection
What are TH1 cells and how do they develop from naive CD4 cells?
TH1 cells help control viral infections and bacterial intravascular infection of macrophages e.g. leprosy, TB that hide from MHC- 1 antigen presentation
- The viruses and intravascular bacterial infections induce IL-12 secretion by dendritic cells
- This can activate NK cells to produce IFNg
- Naive CD4 T cells are activated in the presence of IL-12 and IFNg and differentiate into TH1 cells
How do TH1 cells protect the body from disease?
Some infections e.g. mycobacteria hide in phagosomes – protects them from MHC-I antigen presentation
But peptides from these bacteria will be presented by MHC-II - this is because macrophages are professional APCs
Recognition of peptide/MHC-II on an infected macrophage causes Th1 cell to produce IFNg
TH1 TCR binds to the MHC-2, CD40 ligand binds to CD40 on the macrophage and IFN-g binds to its receptor on the macrophage. IFNg activates the macrophage
Following activation, macrophage will fuse the phagosome (which contains the bacteria) with lysosomes. Reactive oxygen and nitrogen species then kill bacteria – very toxic
Why are macrophages not activated all the time by TH1?
- Requires too much energy
- Results in localised tissue destruction due to release of reactive species
