T cell immunity II Flashcards
what are the “requirements” for positive and negative selection of T cells during development?
T cells with TCRs that can recognize MHC and peptide complex are positively selected - surviving development
T cells with TCRs that recognize MHC and peptide complex with high affinity are negatively selected - likely to be self-reactive cells, therefore, killed
T cells need moderate affinity to survive
describe the development process of TCRs from the genes
note, the 4 gene loci: alpha, beta, delta, gamma
in TCR development… beta rearranges first, TCR alpha second!
TCR beta chain can pair with “pre-T alpha” (unrelated to TCR alpha, it’s just a place holder) and other proteins to form pre-T receptor
—— an important checkpoint in early T cell development
what are the proteins used to assist T cell signal transduction? why does the T cell need to be assisted?
TCR can’t do it by itself because of the short cytoplasmic tail
the complex of these proteins that assist is called CD3 (cluster differentiation) and is only found in T cells
briefly describe the development of T cells in the thymus
can be divided into 3 stages
- double negative
- double positive
- single positive
T cell initially doesn’t have either CD4 or CD8, therefore, called double negative
then, they become double positive cells, expressing both CD4 and CD8
——- at this stage, they can interact with both MHC II/I
later, they make a decision to shut off one of the them, becoming single positive
go into more depth on the double negative phase of T cell development
DN 1
DN 2
TCR beta-chain locus rearrangement (at the DNA level)
—— if successful, it encodes for the TCR beta chain which will go to the cell surface as pre-TCR with a pre-T alpha molecule
DN3
beta-selection
—— checkpoint!: **initiated by pre-TCR signalling which means successful beta-chain rearrangement – below are the effects of the signal and what makes up beta-selection
—— induces TCR alpha-chain locus rearrangement
—— stimulates expression of CD4 and CD8 coreceptors on the cell surface
—— stimulates proliferation
—— stops additional TCR beta-chain locus rearrangement on the other allele; so only one beta-chain allele rearranges/is rearranged… referred to as allelic exclusion
in the double negative phase of T cell development, what does the pre-TCR signalling cause?
beta selection! which includes:
induces TCR alpha-chain locus rearrangement
stimulates expression of CD4 and CD8 coreceptors on the cell surface
stimulates proliferation
stops additional TCR beta-chain locus rearrangement on the other allele; so only one beta-chain allele rearranges/is rearranged… referred to as allelic exclusion
go into more depth on the double positive phase of T cell development
TCR alpha-chain rearrangement
DP
—– high affinity costimulation -> negative selection
go into more depth on the single positive phase of T cell development
SP
—– intermediate affinity costimulation -> positive selection
—– double positive T cells are selected for by MHCII/I, resulting in a single positive T cell that represents either CD4/CD8
T cell will leave the thymus and migrate to lymph nodes of the body
describe the rearrangement of TCR/BCR genes that result in the variable region’s amino acid diversity
note that TCR/BCR genes are a long chain of nucleotides compared to others
loci contains various segments; V, D, J, C
V, D, and J segments make up the variable regions thru alternative splicing – rearrangement
C segment makes up the constant region which has no diversity
where does positive and negative selection occur in the thymus for CD4 and CD8 T cells? describe this process
CD4 and CD8 T cells are positively selected in the cortex and negatively selected in the medulla by thymic epithelial cells
at the cortex, the double positive T cell needs to receive a signal or else they will die (death by neglect)
—– majority of T cells have TCRs that don’t recognize anything – because TCR recombination is sloppy
—– huge rate of cell death in the thymus! approx 90%
if TCR has high affinity for MHC and peptide, it will undergo negative selection and T cell is killed
—– because it’s a self antigen, activating the tolerance mechanism
TCR with a moderate affinity will undergo positive selection and survive
—– T cell decides to down regulate CD4 or CD8 and then moves into the medulla
where in the thymus does T cell activation occur (where do T cells mature)?
in T cell zones of the lymph nodes, T cells can recognize antigen presented by dendritic cells
T cells are activated by dendritic cells and differentiate into effector cells, now able to initiate an immune response
what are the 3 signals that T cells require for activation?
all 3 must be present for full activation
1) TCR binding to antigen/MHC
2) costimulatory receptors
3) cytokines
—- can come from APCs (paracrine: between nearby cells)
—- can come from T cell (autocrine: from a cell to itself)
describe T cell tolerance induction by anergy
self tolerance mechanism activated by APCs
anergy is when all 3 activation requirements have not been met
anergic T-cell continues thru circulation without activity – nothing happens due to lack of costimulatory activity and cytokines from the non-APC
serves as a checkpoint, stopping autoreactive T cells
what changes does T cell activation induce?
metabolic changes and turns genes on/off, preparing the T cell for cell division and differentiation into effector cells
CD4 -> helper T cell
CD8 -> cytotoxic
describe the killing mechanism of cytotoxic T cells
cytotoxic T cell approaches target cell that has an MHC I presenting the virus peptide
the CD8 T cell can recognize this because it’s already been activated and licensed to kill by dendritic cells
later, granules will congregate to the area where the cytotoxic cell and target cell are in contact
granules will release into the target cell, it’s contents killing the cell
—— these granules contain perforin (how NK cells kill) which allow other proteins to enter and kill the cytotoxic cell
