MHC Class I Pathway

MHC Class I Pathway

1. -CD8+ cytotixic T lymphocytes (CTL)

   • Surveillance system-destroy abnormal (virally infected cells)

2. CD8+ CTL detection of virus infected cell

   • T cell receptor on the CD8+ CTL recognises the MHC/peptide complex, antigen peptide is bound to MHC on an APC
     • MHC class I molecules are present on all nucleated cells-so all cells in body can be recognised by T cells
     • If antigen is from foreign or abnormal protein that CTL destroys the cell
       • any self reacting T cells are destroyed in T cell development so only left with ones that detect foreign cells
     • viral antigens expressed within the cytosol of the infected cell (endogenously) are degraded by PROTEOSOME COMPLEX
       • Proteosome-core structure (20S proteosome)-4 discs (2 alpha, 2 beta) made up of 7 subunits-3 of beta subunits contain active sites
         • proteins targeted for degradation=addition of ubiquitin-19s recognises these proteins=unfolded & fed through centre of core particle=degraded
           • Generates peptide of ~5-15 AA
       • Constitutive proteosome n all cells- IFN-gamma produced when infected by virus=causes 3 active site subunits to be replaced by LMP2, LMP7 & MECL-1
         • =changes proteolytic specificity of proteasome to form IMMUNOPROTEASOME-diff set of peptides generated which are lysed by CD8+(normal ones aren't)
   • How do peptides get from cytosol to the ER?
     • TAP-heterodimer forms channel so peptides of 8-13 AAs can go across ER men
       • TAP=ATP-binding cassette (ABC) family of transporters- hereodimer complex of TAP1&2-cells deficient in TAP cant present antigen to CD8+
     • Peptide binding to MHC
       • peptide binding groove between alpha1 & 2 alpha-helices-peptide is bound with both ends tightly bound at either side of cleft
         • Bind peptides mostly 8-9AA, peptide motifs been found for each HLA allele studied=specific binding
           • MHC I heavy chains first associated with CALNEXIN-heavy chain folds to form capable of binding beta2-microglobulin-calnexin replaced with calreticulin
             • TAPASIN & ERp57 associate with complex-generate PLC=MHC can bind peptides & MOVE THROUGH GOLGI TO CELL SURFACE
   • Peptides further trimmed in ER
     • trimmed down to 9 AA one because proteosome recognises 15 AA, TAP recognises 8-13-MHC only binds 9AA

3. MHC class I encoding genes found on ch 6- also known as human leucocyte antigen (HLA) system

4. Cytotoxicity/chromium release assay

5. Source of protein

   • eg. DRiPs-source of protein for MHC-defective ribosomal products-allow early detection of virally infected cells (degraded by proteosome very quickly)
   • correct proteins take longer to be degraded by proteasome
   • OAPs?
   • Exogenous antigens can be presented on MHC class I by professional APCs: ALTERNATIVE PATHWAY
     • Exogenous antigens taken up by dendritic cell- either by phagocytosis
       • or they may find direct access across ER-sec61 drives them back into cytosol where degraded by proteasome into peptides etc...