Antigen Processing and Presentation
Chapter 8
Antigen Recognition by T Cells • T cells recognize linear peptides not whole proteins. • T cells only recognize epitopes when they are complexed to
MHC molecules. • Therefore protein antigens must be processed and
presented by other cells to be recognized by T cells. • This process is referred to as antigen processing and
presentation. – Note: the association of antigenic peptides w/ MHC is a
saturable, low-affinity interaction (Kd ~10-6M) with a slow off/on rate.
• In general CD8+ T cells recognize endogenous antigens and CD4+ T cells recognize exogenous antigens.
• MHC molecules bind multiple peptides, however each T cell only recognizes one peptide.
Assays for T cell Activation
Antigen
APC Th cells Tc cells Macrophage Dendritic Cell B cell
APC + Th + Ag
Proliferation (3H-thymidine uptake)
Tc + Target cell +Ag
Target cell lysis (51Cr release)
“Primed T cells”
T cells Macrophage
Figure 10-18
Kloetzel, P.M., Nat. Immunol., 2004
Proteosome Produces Epitopes Poorly
Ackerman and Cresswell, Nat. Immunol., 2004
Proteosome Produces Epitopes Poorly
Ackerman and Cresswell, Nat. Immunol., 2004
Epitope Destruction vs. Production
Epitope Destruction vs. Production
Proteosome Produces Epitopes Poorly
Ackerman and Cresswell, Nat. Immunol., 2004
Ackerman and Cresswell, Nat. Immunol., 2004
Peptide Loading Complex (PLC)
HLA-DM/H-2M • Acts as a catalyst to enhance the release
of CLIP • Does not bind antigenic peptides so does
not act as a peptide transfer molecule • Most efficient at low pH • Acts as a peptide editor, facilitating the
exchange of low stability, high off rate peptides for high stability peptides with a low off rate
Role of DM in Peptide Loading
Brocke et al., 2002
Interaction of DM and DO
Denzin et al., Science, 1997
[DM]
DM + DO
Stability in SDS correlates with affinity for the bound peptide; binding to CLIP is of low affinity
HLA-DR3αβ-CLIP + peptide + HLA-DM +/- HLA-DO
t1/2= 26h
t1/2= 86h
t1/2= 1h
t1/2= 65h
MHC Class II Peptide Stability Affect T cell Stimulation
Cross-Presentation
• Refers to the presentation of exogenous antigens on MHC class I molecules.
Cross-Presentation
• Refers to the presentation of exogenous antigens on MHC class I molecules.
• Exact mechanism is unclear; two models have been proposed: recycling and ER loading.
Cross Presentation Models
Jensen, 2007
Cross-presentation: ER Model
Direct access to the ER via transiently available continuities
Ackerman and Cresswell, Nat. Immunol., 2004
Cross-presentation: Phagosome Model
Sec61 associated phagosome
Ackerman and Cresswell, Nat. Immunol., 2004