T cell biochemistry Flashcards
the immune system cells all start life where
life in the bone marrow, receiving signals from stromal cells
describe T cells
Mature in the Thymus
Regulatory and Cytotoxic
Can further differentiate depending on specific signals
describe B cells
Mature in the Bone Marrow
Produce antibodies
describe NK (natural killer) cells
Mature in the Bone Marrow, but also secondary lymphoid tissues
Cytotoxic
describe antibodies
Antibodies illicit a strong immune response, coordinating many cells of the immune system, and B-cells can develop an immune memory to help in times of further infection.
name some things antibodies cannot be used to combat effectively.
Intracellular pathogens
- Bacteria and Viruses
- Tumours
what does the immune system need to work efficiently
T cells
explain the T cell receptor
Approximately 105 T-Cell receptors on the surface of the T-cell
Consists of 2 polypeptide chains:
- Majority - ⍺β T-cells
- Minority - 𝛾δ T-cells
Each chain has 2 domains, V (Variable) and C (Constant), which are linked by a disulphide bond
Hydrophobic transmembrane domain and a very shot cytoplasmic tail
describe some differences between TCR and fab
Antibodies:
Broad sheets of anti-parallel β-sheets
- Hydrophobic side chains are tightly packed between the sheets and held together with disulphide bridges
- Alpha helix is towards the back of T cell receptor
C⍺:
Half of the domain, that closest to the β chain, forms a β-sheet
The other half is made up of loosely packed strand and a short stretch of ⍺-helix
- Held to the one of the strands of the β-domain to this helix
Additionally, the interactions between C⍺ and Cβ is assisted by carbohydrates
- Carbohydrate on C⍺ forming hydrogen bonds with the amino acids of Cβ.
CDR loops:
Fairly similar between an antibody and the TCR, some displacement
V⍺ CDR2
- At a right angle compared to the equivalent loop in the equivalent loop in an antibody.
TCRs have a 4th hypervariable region away from the antibody binding site
explain the T-cell receptor gene rearrangement on TCR⍺
similar to the Immunoglobulin light chain
V and J segments
explain the T-cell receptor gene rearrangement on TCRβ
similar to the immunoglobulin heavy chain
V, D, and J segments
when do genes in T cells rearrange
during T-cell development in the thymus in a process similar to the Germinal Centre Reaction for B-cells
do T cell receptors bind antigens directly
no
antibodies bind what in the circulation
and make contact with what
bind antigen in the circulation, whether that be free flowing or on the surface of the pathogen
Make contact with discontinuous amino acids only brought together when the antigen is in its tertiary structure
what do T cells bind to
to an antigen-protein complex
what is an antigen-protein complex
Short, continuous amino acid sequences from an unfolded protein
Presented as part of a protein complex on the surface of an antigen presenting cell
what does MHC stand for
Major Histocompatibility Complex
how are MHC 1 and MHC 2 similar and different
Closely related in overall structure and function, but differ in their protein subunits
- 2 paired domains nearest the membrane resemble an immunoglobulin
- 2 domains furthest from the membrane produce a peptide-binding cleft
explain MHC 1 structure
2 Polypeptide chains
- The ⍺-chain, which makes up 3 domains of the protein and crosses the membrane and forms the entire peptide binding cleft
- Β2-microglobulin associates with the ⍺3 domain
explain MHC 2 structure
2 polypeptide chains
- Both the ⍺ and the β chain cross the membrane
- The peptide binding cleft is made up of both the ⍺ and the β chain
In order to stimulate T-cells, MHCs need to be what
able to bind a large variety of peptides
Unlike other peptide-binding receptors such as GPCRs
MHC proteins are unstable when not bound to a peptide
- MHC-I binds peptides 8-10 amino acids in length
- MHC-II can bind peptides of any length
MHC-I binds and presents what
intracellular peptides that reside in the cytosol
Some pathogenic bacteria, and some protozoa, reside inside vacuoles once inside the cell and peptides are presented on what
MHC 2
Extracellular pathogens are phagocytosed, and peptides are presented on what
MHC 2
describe cross presentation
Some pathogens will not infect phagocytic antigen presenting cells (such as dendritic cells), for example the epithelium
Thus, the antigen presenting cell will express MHC-I presenting peptide antigens from the infected cell
name some T cell co receptors
CD4 +
CD8+
describe the T cell co receptor CD4+
T-helper cells
Recognises MHC-II
describe the T cell co receptor CD8+
Cytotoxic T-cells
Recognises MHC - 1
describe T cell co receptors
TCR binds directly to the MHC peptide binding cleft
CD4 and CD8 bind to an invariant site away from the peptide binding cleft
The TCR⍺β heterodimer, along with either CD4 or CD8 is not sufficient to initiate what
activation of the T cell
what 2 things are needed for TCR signal transduction
CD3 complex
ζ-chain – zeta
what is CD3 complex made up of
CD3𝛾
CD3δ - delta
CD3ε - epsilon
TCR signal transductions signalling is initiated by what
initiated by ITAMs in the 𝛾, δ, ε, and ζ chains
- Immunoreceptor Tyrosine-based Activation Motifs
- CD3𝛾, δ, and ε all have 1 ITAM
- ζ chain has 3
in TCR signal transduction, Each ITAM has 2 Tyrosine residues
what happens to these
Become phosphorylated by tyrosine kinase Lck, which is colocalised with the CD4/CD8 coreceptor, when the receptor binds its ligand (MHC + peptide)
Phosphorylation leads to the recruitment of Zap70
what next happens in TCR signal transduction, to Zap70
phosphorylates LAT (Linker for Activated T-cells), which leads to the recruitment of PI 3-kinase
in TCR signal transduction, what happens after the recruitment of PI 3-kinase
the T-cell signal branches into distinct modules, leading to the activation of different transcription factors with different effects
during TCR signal transduction different transcription factors with different affects are activated, name these and describe them
NFκB – the master inflammatory transcription factor
AP-1 – differentiation, proliferation, and apoptosis
NFAT
- Requires Calcium influx
- Family of 5 proteins differentially expressed in different tissues
- For T-cells, NFAT is important for activation and the production of specific signalling molecules
Derived from the bone marrow, but all the development happens where
in the thymus
what happens in T cell maturation
Similar to B-cell maturation:
- Gene re-arrangement
- Testing of the new receptor
- Release of the new T-cell or - cell death
Round of positive and negative selection
- Dependent on Notch signalling
CD4+ T-cell produces different subtypes depending on what
the signal
what are the subtypes CD4+ T-cell produces
Tfh – B-cell formation
Th1 - type 1 response. intracellular bacteria, protozoa, and viruses. autoimmunity
Th2- type 2 response. extracellular helminths and venoms. allergy and asthma
Th17 - type 3 response. extracellular bacteria and fungi. autoimmunity
Treg- immune tolerance. immune regulation
CD4 CTL? - MHC2-dependent. killing
what are CD8+ subsets
cytotic lymphocytes
- MHC 1 dependent
- killing
explain CD8 Cytotoxic T-cells
Kill cells by inducing cell death by either intrinsic or extrinsic pathways of apoptosis:
- Extrinsic – binding of Death Receptors
- Intrinsic – Mitochondrial degradation
Both require Caspase enzymes:
- Proteases
- Initiator Caspases
Promote apoptosis by cleaving and activating other caspases
Intrinsic = Caspase 9
Extrinsic = Caspase 8 and 10
Effector Caspases
- Initiate the cellular changes associated with apoptosis
- Both pathways use Caspase 3, 6, and 7
