Lecture 6 - T cell response Flashcards
How is the antigen binding region of the TCR generated?
By rearranging gene segments of the alpha and beta chain. B chain locus has VDJ regions, A has just VJ regions
In what order is the TCR rearranged?
B rearranged first then alpha
How do antigen binding regions compare between Ig and TCR?
Both have three CDRs in Vh, Vl and Va Vb
How do on and off rates compare between Ig and TCR?
Ig cells have higher affinity that changes over immune response. T cells have lower affinity which doesn’t change
Where do T cell precursors originate then develop?
Bone marrow then develop in thymus
How is the gamma-delta T cell receptor different from the alpha-beta?
Gamma-delta respond to lipid not peptide. Make up the majority of T cells in epithelium
What accessory proteins are necessary for T cell binding?
CD4 or CD8 simultaneously with MHC
What can double negative CD3/4/8 cells become?
gamma-delta CD3s, or if pre-TCR rearrangment is functional, double positive pre-TCRs
What happens to most of the double positive TCRs?
95% apoptose, dye by neglect
What happens to the double positive TCRs that do not die by neglect?
If they bind one CD just right they downregulate the other one and become single positive thymocytes which are exported to the periphery and mature as T cells. If they bind too strongly to either CD, they die by neg selection
Which cells present peptide-MHC complexes to double positive thymocytes?
Thymic epithelial cells
What are the two types of CD4 cells can CD4 T cells become?
Can become effector CD4 T cell (which can activate macrophages, B cells, other cells) or a memory CD4 T cell
What are the two kinds of CD8 T cells can naive CD8 cells become?
Can become effector CD8/cytotoxic T lymph or memory CD8 T cell
What is the role of CD3 in T cell activation?
CD3 chains are expressed along with the TCR and are responsible for initiating signal transduction/informing the cell that antigen has been bound
What happens after CD4/CD8, TCR and CD3 are all activated?
Signal transduction which starts with the stimulation of Lck and ZAP-70 which eventually leads to the expression of transcription factors like NFAT, NF-kB and AP-1
What happens if a T cell is only stimulated at the TCR by antigen/MHC?
Anergy/unresponsiveness
What is the second signal necessary for T cell activation?
Co stimulation via binding of CD28 on T cell to B7 on APC
What happens if a T cell only recieves co-stimulation?
Nothing, no effect.
How is B7 upregulated on APCs?
Cytokines from other activated cells or by products of microorganisms stimulate pattern receptors on the APC
What is the role of CD40:CD40L interactions in T cell activation?
Positive feedback loop between the APC and the T cell. T cells activated via MHC/ag and B7/CD28 express CD40L which binds to CD40 on APC which causes APC to upregulate B7 expresssion leading to more effective T cell stimulation
What is the role of CTLA4 in T cell activation/suppression?
CTLA4 is a negative regulator expressed late in T cell activation. After CD28 co-stimulates it induces expression of CTLA4 which binds B7 with higher affinity and delivers inhibitory signals to activated T cells
How does TCR stimulation lead to increased adhesion between T cells and APCs?
Promotes clustering and increased affinity of integrins
What receptor/ligand is required for T cell proliferation?
IL 2 and its receptor.
What are the two forms of IL-2 receptor and where/when are they expressed?
Low affinity two chains (B and G) and a high affinity with a third chain A. Low affinity expressed on naïve T cells (cant proliferate), High affinity expressed after TCR stimulation and can accept IL-2 made by activated T cell and neighboring cells
How do cytokine receptors initiate biochemical signals?
Through dimerization and autophosphorylation of JAK which leads to activation of STATS that translocate to the nucleus to effect transcription
Where do mature T cells circulate?
Through secondary lymphoid organs
What happens if mature T cells have a strong TCR recongition in the secondary lymphoid organs?
Stimulated to proliferate and differentiate into effectors. Re-enter the circulation and migrate to site of infection where they bind to adhesion molecules in vascular endothelial cells so they can leave circulation for the infected tissue
What do effector CTLs activated by antigen/MHC recognition no longer need? And what do they do?
No longer need costim. Signals delivered by TCR lead to release of granules towards the target cells
What do CTL granules contain?
Perforin which forms pores in the target cell membranes. Granzymes which activate capsases (cleave target cell proteins) which enter through pores formed by porin.
What happens if a virus is unable to infect a dendritic cell/other APCs per se?
Able to cross-present. Can present exogenous antigen to MHC class I restricted CD8 T cells using the exogenous processing machinery
What does IFN-y secretion from CD4/8 and NK T cells do?
Actiate macrophages
What does TGF-B secretion from CD4 regulator T cells and other cells do?
Inhibit T cell activation; cause differentiation of regulatory T cells
What are the different subsets of CD4/helper T cell effectors and the cytokines that stimulate them?
Th1 via IFNy for intracellular pathogens. Th2 via IL-4 for parasitic worms (stimulate B cells to make IgE/G and via IL-5 recruit eosinophils). Th17 via IL-6 (plus TGFB) for extraceullar bacteria (can predispose to autoimmunity). aTreg via TGFB only for counter regulation
What do TH1 cells secrete and stimulate (along with T-bet tx factor)?
IFNy Activate macrophages and stimulates B cells to make IgG for opsonization
What do TH2 cells secrete and stimulate (along with GATA3 tx factor)?
Secrete IL4 which stimulates B cells to make IgG and IgE. Secrete IL4/13 to stimulate alternative macrophage to stimulate tissue repair/fibrosis. Secrete IL-5 to activate eosinophils
What do Th17 cells secrete and stimulate (along with RORy tx factor)?
IL-17 which acts on cells to produce chemoattractants for neutrophils. IL-22 which improves barrier function of the epithelium (esp in intestinal tract)
What happens if Th1 is overexpressed?
Inflammatory conditions
What happens if Th2 is overexpressed?
Allergy, asthma
What happens if Th17 is overexpressed?
Autoimmunity
What happens if regulatory cells are overexpressed?
Diminished immune responses against tumors
What happens to effector T cells that don’t die at the end of the immune response?
Become memory T ccells
Where are memory cells found?
In circulation and in secondary lymphoid organs
