antigen processing and presentation - cancer treatment · antigen processing and presentation...
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Antigen Processing and Presentation
Chapter 8
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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.
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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”
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T cells Macrophage
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Figure 10-18
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Kloetzel, P.M., Nat. Immunol., 2004
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Proteosome Produces Epitopes Poorly
Ackerman and Cresswell, Nat. Immunol., 2004
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Proteosome Produces Epitopes Poorly
Ackerman and Cresswell, Nat. Immunol., 2004
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Epitope Destruction vs. Production
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Epitope Destruction vs. Production
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Proteosome Produces Epitopes Poorly
Ackerman and Cresswell, Nat. Immunol., 2004
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Ackerman and Cresswell, Nat. Immunol., 2004
Peptide Loading Complex (PLC)
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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
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Role of DM in Peptide Loading
Brocke et al., 2002
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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
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t1/2= 26h
t1/2= 86h
t1/2= 1h
t1/2= 65h
MHC Class II Peptide Stability Affect T cell Stimulation
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Cross-Presentation
• Refers to the presentation of exogenous antigens on MHC class I molecules.
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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.
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Cross Presentation Models
Jensen, 2007
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Cross-presentation: ER Model
Direct access to the ER via transiently available continuities
Ackerman and Cresswell, Nat. Immunol., 2004
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Cross-presentation: Phagosome Model
Sec61 associated phagosome
Ackerman and Cresswell, Nat. Immunol., 2004
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