03/06b MHCs & T Cell Receptors Flashcards
How are antigens recognized by T cells?
Antigens must be degraded into peptides in antigen-presenting cells, and presented to T cells on MHC molecules
T cells recognize these peptides through T cell receptors
What are the two classes of MHC molecules? How do they differ?
MHC I and MHC II
They have distinct cell distributions and functions, and are recognized by distinct subsets of T cells
What determines which MHC will present the antigen?
Source and location of the antigen
Which MHC displays cytoplasmic antigens? What types of cells does it activate?
MHC I - displays viral proteins found in the cytosol
Activates CD8 T cells to mature into cytotoxic T cells
Which MHC displays endocytosed vesicular antigens? What types of cells does it activate?
MHC II - displays proteins that have been endocytosed (from extracellular bacteria or toxins)
Activates CD4 T cells to mature into helper T cells, which in turn activate macrophages and B cells
What cells express MHC I?
All cells!
What cells express MHC II?
Antigen-presenting cells
Describe the interaction of antigen to MHC receptor
Peptides do not readily dissociate from MHC receptors
Peptide binding contributes to the stability of the MHC receptors
Describe the specific binding between MHC I and their peptides
Limited peptide length (8-10 amino acids) due to the MHC binding pocket
Key amino acids in the peptide serve as anchors (degenerate specificity)
Describe the specific binding between MHC II and their peptides
Peptides can be 13 amino acids or longer, due to the open ends of the binding pocket
Peptide backbone interacts with conserved amino acids in the binding pocket
What are the three MHC I genes?
HLA-A
HLA-B
HLA-C
What are the three MHC II genes?
HLA-DR
HLA-DP
HLA-DQ
How many MHC I proteins do you express? Why?
Six different MHC I proteins - two different inherited alleles for each class of MHC I This provides an increased capacity for peptide binding and presentation
Predilection for a large number of autoimmune diseases can be predicted from WHAT?
Specific MHC Class II alleles
How are peptides loaded onto MHC I?
Proteins are degraded to peptides by the proteasome complex
Peptides are delivered to the ER from the cytosol by TAP, and loaded onto MHC I molecules
MHC I is released from TAP and transported to the cell membrane
What distinguished the constitutive proteasome from the immunoproteasome?
The immunoproteasome has specific subunits that are induced by interferon
Interferon can also induce the proteasome to generate peptides that have an affinity for MHC I
How do viruses interact with the MHC I processing pathway?
Block it in order to evade the immune system
Different viruses can interfere with peptide transport or peptide loading, or degrade the MHC molecules themselves
How are peptides loaded onto MHC II?
Proteins are endocytosed and degraded in acidic endosomes
MHC II molecules are synthesized in the ER, but blocked from binding to any peptides by an appendage protein until they reach the endosome
MHC I is then transported to the cell membrane
What is antigen cross-presentation?
The ability of dendritic cells to endocytose viral particles and present them on MHC I in order to activate cytotoxic T cells
Necessary for viruses that do not infect dendritic cells
Antigens are endocytosed and digested in the vesicular compartment, then transported into the cytoplasm and eventually to the ER to be processed and presented on MHC I
What happens if you lack MHC I function?
Bare Lymphocyte Syndrome Type I
Patients tend to have chronic bacterial respiratory infections
Can be treated with antibiotics and IVIG
What happens if you lack MHC II function?
Bare Lymphocyte Syndrome Type II
Patients present with recurrent bacterial, viral, fungal and protozoal infections in the first year of life
Fatal unless treated with a bone marrow transplant
What are class I-like CD1 molecules?
Molecules that are homologous to MHC I, but possess a large hydrophobic binding pocket
Bind primarily to lipids
Present pathogen-derived lipids to T cells, and both self and pathogen lipids to NK cells (have an innate-like function)
How do TCRs carry out signal transduction?
Through the CD3 complex - cytoplasmic tails (ITAMs) recruit tyrosine kinases
What are TCR co-receptors? What is their function?
Molecules that are required for effective TCR signaling, and bind to MHC simultaneously with TCRs
CD4 is expressed on helper T cells and binds MHC II
CD8 is expressed on cytotoxic T cells and binds MHC I
What is MHC restriction?
The recognition by T cells of self MHC proteins complexed with antigen peptide
During development, only T cells that interact weakly with self MHC proteins are selected
How are alloantigens recognized in the context of a tissue graft?
Indirectly - alloantigen peptides are presented by self MHC proteins on recipient APCs, and provoke a minor immune response
Directly - intact allogeneic MHC on donor APCs is recognized, which provokes a strong T cell response
Why do alloantigens provoke such a large immune response?
Host T cells that recognize self-MHC complexed with foreign peptides may have the capacity to cross-react and recognize allogeneic MHC complex with any peptide
Allogeneic grafts express MHC with MANY peptides, thus activating many cross-reactive T cells
What are superantigens?
Whole proteins (NOT peptides) expressed by some bacteria and viruses
Bind to MHC class II molecules outside their binding sites, and to particular TCRs
This results in cross-linking and a potent T cell response (ALL cells that express that particular TCR)
Not an antigen-specific response
What are the consequences of superantigen stimulation?
HUGE T cell response (up to 20%)
Massive interferon release, macrophage activation, and cytokine storm
Lots of T cells die
Disrupt your normal immune response - good for bacteria, bad for you
List three examples of bacterial superantigens and the disease they cause
Staph enteroxin - food poisoning
Toxic shock syndrome toxin - TSS
Exfoliative toxins A & B - Staph scalded skin syndrome
