Adaptive Immunity T Cells 3 Flashcards
What is the T cell selection process in the thymus?
Process by which CD4 Helper cells and CD8 cytotoxic cells are selected so they can migrate from the thymus to peripheral tissue to exert the immune response.
What mechanisms does the immune system use to produce required diversity in T cell antigen specificity?
gene rearrangements and mutagenesis
Give the process for the T cells producing different antigen receptors
In the gene locus which codes for the variable antigen binding domain of the T cell receptor alpha chain, there are 55V and 61 J segments.
To form a functional exon which encodes for the entire sequence of the alpha chain antigen binding domain, one of the V and one J segment must be brought together.
This involves rearrangement of the chromosome of this locus by looping DNA, randomly aligns a V and J segment and followed by an insertion of DNA and re-ligation will from a continuous functional exon.
The J segment codes for the most of the C terminal part of the alpha chain antigen binding domain. There may be some contribution from the B segment. The loop makes most of the contact with the highly variable antigenic peptide, bound by MCH 1 or 2.
By combining any V and J segment, recombination can potentially make 3500 different exons which code for the alpha chain antigen binding domain.
The beta chain locus has fewer J segments (2 copies of an additional D segment as well as J segments). In this case, recombination of any of the V segments with the either of D segments with any J results in approx 1500 different combinations. DJ segment codes for the C terminal loop which makes most contact with the antigenic peptide in the Beta chain.
What 2 processes give T cell receptors diversity within the loci?
- Recombinatorial diversity (Since any alpha chain can combine with any beta chain, these two gene loci can potentially code for a few million different T cell antigen receptors.)
- Addition of nucleotides at recombination sites (At each of the V, J or D sites, they are cut by endonucleases, additional nucleotides are added enzymatically to the 3 prime strand in a random manner.)
What problems do T cell receptor diversity bring?
Mechanisms are random and many of the T cells produced have T cell receptors that can’t bind to MHC complexes or can recognise self-antigens so could be harmful.
How does positive selection of T cells occur in the thymus cortex?
Immature T cells in the thymus have a expression of the antigen receptor and both cd4 and cd8 (double positive cells).
In the cortex, the cells undergo positive selection to enrich for cells that have antigen receptors that bind to self MHC.
The immature T cells are exposed to thymic cortical epithelial cells and dendritic cells that express both MHC 1 and 2. Those cells that have antigen receptors capable of binding to these proteins receive a surviving signal. Those which cannot bind to self MHC undergo apoptosis. If they bind to MHC class 1, they maintain expression of CD8 and lose it for CD4 and become cytotoxic T cells and vice versa to become T helper cells (CD4 expression and lose CD8).
Double positive cells that bind to MH2 becomes T helper cells and migrate to the thymus medulla. Double positive cells that bind to MHC 1 become single positive CD8 T cells and migrate to the medulla.
How does negative selection work in the medulla of the thymus?
Used to remove T cells that recognise self antigens in the medulla.
In the medulla, the T cells that have surfaced positive selection in the cortex are exposed to MHC complexes with self antigen from the surface of medulla epithelial cells and dendritic cells.
T cells which bind with low affinity with survive. Those with high affinity undergo apoptosis or become regulatory T cells. These inhibit immune responses in an antigen specific manner so will lower the response to self antigens.
Cells that bind with lower affinity will survive and migrate to peripheral tissues and provide protection against infection.
