antigen processing and presentation - cancer treatment · antigen processing and presentation...

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