T-cell Antigen Recognition and Development - Kane Flashcards
What is a T-cell in general (phenotype/function)?
T-cells generally express CD4 or CD8 and engage with MHC (I and II bound to peptides) via their TCR to initiate immune effector or regulatory function.
Describe some T-cell effector functions.
T-cells recognize foreign peptides presented on MHC and can stimulate B-cell antibody secretion, secrete cytokines to stimulate leukocytes, and directly kill virally infected cells.
What are the subsets of T-cells and what do they recognize?
Alpha/beta T-cells can only bind MHC-peptide antigen. Gamma/delta T-cells have more flexibility being able to recognize lipid or whole protein. There are also Tregs.
What are the subsets of alpha/beta T-cells?
CD4+ (helper) and CD8+ (killer) T-cells.
Which MHC is typically recognized by CD8+ T-cells?
Class I
Which MHC is typically recognized by CD4+ T-cells?
Class II
What is MHC restriction?
This means that a T-cell must both recognize its cognate peptide in the context of MHC.
In the TCR loci, where is the greatest source of diversity?
CDR1,2,3 regions (complementarity determining regions) especially CDR3. This is where N- and P-nucleotide addition can occur.
What is combinatorial D-joining?
Process during recombination where two D segments are joined before J segment is added. Extra diversity.
Does N-region addition occur in Ig’s and TCRs? If so, where?
Yes, in Ig’s this only occurs in the heavy chain whereas all TCR genes do this.
Can T-cells undergo class switching?
No.
Why are CDRs of the TCR chains critical to TCR binding?
They are highly variable regions that are directly binding to MHC-antigen during T-cell recognition.
Where does CD4 and CD8 engage with MHC?
They stabilize TCR interaction with MHC by binding to non-polymorphic regions of MHC.
How are the components of TCR assembled?
They are transcribed and translated separately and assembled in the ER. They configure on the surface of the cell mediated by charge residues in the TM regions. The full complex must be present for surface expression.
Affinity of Ig vs. TCR
Ig’s have a much higher affinity for ligand than TCR.
What if TCR does not recognize (bind) MHC?
No immune response
What if TCR recognizes self-MHC too strongly?
Autoimmunity
Where are early T-cells derived and where do they develop?
T-cell progenitors come from the bond marrow and develop in the thymus.
First step of T-cell development.
VDJ recombination of the Beta chain occurs and is trafficked to the surface to form a pre-TCR.
Second step of T-cell development.
VDJ recombination of the alpha chain and pairing with the beta chain on the surface.
Where are T-cells early in development in the thymus located? What does the thymus epithelium do?
The thymocytes are tightly packed in the cortex of the thymus. Thymic cells present antigen to developing T-cells.
Describe the classic experiment regarding MHC restriction in the thymus.
The key concept is that T-cells will only recognize antigen in the context of MHC.
- Remove MHC heterozygous mouse (a/b) thymus
- Lethal x irradiation to kill bone marrow stem cells.
- Graft in a homozygous b mouse thymus and a/b stem cells – immune reset w/ different thymus.
- Infect with LCMV to illicit CD8+ T-cell response.
- Take CD8 T-cells from spleen and see if they can destroy type A or B cells infected with LCMV.
New T-cells coming from the bone marrow cannot recognize A type MHC because they were trained with a B type thymus. T-cells need to be able to recognize YOUR MHC.
Control, infect A/B mouse and see if its T-cells can destroy both a/b cells.
Describe thymic development of T-cells by tracking CD4/8 co-receptors.
- Progenitors enter the thymus as double negative (DN, no CD4/8).
- After TCR assembly, they divide and express both CD4 and CD8 (DP). If TCR assembly fails or has weak binding, the T-cell undergoes negative selection. High affinity TCR T-cells will also die.
- T-cells come out either CD8 or CD4+
What does the pre-TCR do?
Signals successful B-chain rearrangement and tells cell to not rearrange again (allelic exclusion). Signals to express co-receptors and begin A-rearrangement.
