Download T cell receptor

PHM142 Fall 2016
Instructor: Dr. Jeffrey Henderson
Thymus
Helper T-cell
Cytotoxic T-cell
TCR RECEPTOR
ANTIGEN RECOGNITION
TCR RECEPTOR
TCR RECEPTOR
ANTIGEN
RECOGNITION
ANTIGEN
RECOGNITION
Present on all nucleated cells
Foreign
Self
Present on antigen presenting cells (APCs)
•Similar
to the generation of B-cell antigen receptors
•Alpha and beta chains contain Constant and Variable
regions
o V(D)J recombination – Variable, Joining, Diversity genes
o Coordinated by RAG1 & RAG2
o If RAG genes are non-functioning, would lead to Severe
Combined Immunodeficiency (SCID)
o Allelic Exclusion
o No somatic mutation in TCR, compared to B-cells →
Not affinity maturation
1.
TCR binds to antigen
2.
CD45 dephosphorylates intracellular
Src family kinases (Fyn)
CD45
3.
Fyn phosphorylates ITAMS
4.
ZAP 70 binds phosphorylated ITAMS
5.
The coreceptor (CD4 or CD8) binds
too, bringing Lck close which
phosphorylates ZAP 70
6.
ZAP 70 phosphorylates and activates
other intracellular signaling adaptor
proteins, which result in activation of
T cell
•Globular proteins that are resistant to heat
denaturation and proteases
•are produced by many different pathogens
including
bacteria, mycoplasmas, and viruses
•secrete potent toxins that even at very low
concentrations can induce a violent disruption
of the
immune system
•Activate 2-20% of the body’s T cells
1.The soluble superantigen forms a stable interaction with
an MHC Class II molecule
2.A second site on the superantigen binds to the
variable domain of the T cell receptor
3.A third site on the suoperantigen binds to the
T cell’s CD28 (stimulatory co-receptor)
4.The TCR complex is assmebled
5.CD4 T cells are activated and release cytokines
The release of cytokines has 2 main effects on the body:
→Systemic toxicity
→Suppression of the adaptive immune response
Superantigens are responsible for diseases like staphylococcal food
poisoning, staphylococcal toxic shock syndrome, and streptococcal toxic
shock like syndrome
Superantigens also induce apoptosis in the CD4 binding T cells
Drugs Currently Available:
❏Glatiramer acetate
❏Polyclonal human intravenous
immunoglobulins (IVIG)
❏Doxycycline
● TCRs are heterodimers that either contain alpha/beta chains or delta/gamma chains
● Co-receptors determine the class of MHC molecule the lymphocyte will bind to
● CD8 co-receptors confer preference for class I MHC-peptide complexes (cytotoxic T-cell)
● CD4 co-receptors confer preference for class II MHC-peptide complexes (T-helper cells)
● T-cells undergo V(D)J recombination to create a diverse number of TCRs, similar to
Immunoglobulins but they do not undergo somatic hypermutation . This process is initiated by
the enzymes Rag1 and Rag2 which induce double-strand breaks at the border between a
recombination signal sequence and a coding segment.
● Upon binding a peptide presented by an APC via a MHC, the TCR complex is
phosphorylated which leads to the activation of the T-cell by changing cellular expression in
the nucleus.
● Superantigens are protein antigens that can nonspecifically activate up to 20 percent of all of
the body’s T cells resulting in a massive inflammatory response (life threatening)
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