Designing CD8+ T cell vaccines:It`s not rocket science (yet)

Jonathan W YewdellCurrent Opinion in Immunology 2010

... But the review

is ....

CD8+ vaccines

Function of CD8+ T cells:

- clearance of viral infections

- tumor immunity

BUT tumors have good Immune-

Escape strategies

Therapeutic cervical cancer vaccination

CD8+ response

13 diff. HPV peptides + Freud`s adjuvants

HPV induced cervical tumor

Data from: Welters et al., Clin Cacer Res. 2008; Kenter et al., N Engl J Med., 2009

Zur Anzeige wird der QuickTime™ Dekompressor „“

benötigt.

Yewdell et al., Nat Rev Imm, 2003

Activation of CD8+ T cells

Aim: Induction of tumor-specific Tmem for therapeutic cancer vaccination

MHC II

Extracellular antigen

APC

CD4+ T cell

APC MHC I

Intracellular antigen

CD8+ T cell

e.g. bacteria e.g. viruses

MHC I

Cross-presentation

APC

e.g. dying cells, proteins, peptides

CD8+ T cell

Cross-Presentation

MHC I

endolysosome

Vacuolar pathway

Phagosome - to cytosol - pathway

Cat S

TAP

MHC I

ER Proteasome

Vaccine Strategies

What is the desired response?

-What peptides?

- response should be as minimal as possible to avoid side-effects and induction of tolerance

- What Types of CD8+ T cells?

- What anatomic locations should be focused of the response?

How should this response be generated?

- What immunogens should be used

- What dose and

- Which route?

- How many boosts?

Mouse models

BUT mice are still not human

How can we learn from cross-priming?

Zur Anzeige wird der QuickTime™ Dekompressor „“

benötigt.

Yewdell et al., Nat Rev Imm, 2003

(1) MHC I Trafficking

- mod. Cytoplasmic domain no travelling to endolysosome

(2) APC modification

loss of cross-priming via:

- CD8-/CD103- DCs

- injection of proapopt. CytochromeC

- DC preactivation

CD8CD103

(4) Genetic modulation of antigen processing

- KO of endosomal protease IRAP

(3) Drug modulation of antigen processing

- Bortezomib inhibits Proteasome

- Chloroquine enhances cytosolic delivery

Endolysosome

Zur Anzeige wird der QuickTime™ Dekompressor „ “

benötigt.

Zur Anzeige wird der QuickTime™ Dekompressor „ “

benötigt.

Zur Anzeige wird der QuickTime™ Dekompressor „ “

benötigt.

Zur Anzeige wird der QuickTime™ Dekompressor „“

benötigt.

- Proteins favoured

- antigen stability important

- peptides have to metabolically stable

(law of mass action)

-BUT: chaperoned pepetides might

work

- Immnunogenicity highly dependant

on cargo

- e.g adjuvant effect of secreted gp96

Antigen for cross-priming: Proteins vs. peptides

Z u r A n z e ig e w ird d e r Q u ic k T ime ™ D e k o mp re s s o r „ “

b e n ö tig t.gp96

High immunogenicity

Yewdell et al., Nat Rev Imm, 2003

Antigen acquisition in cross-priming

- Cell-delivered antigens

- Nibbling from alive cells

- Phagocytosis of dead cells

- Trogocytosis / „cross-dressing“

-Acquire preformed C1PCs from other APCs during cellular interactions (e.g. from monocytes which phagocytosed dead cell antigens)

- even TCRs can be exchanges between naive T cells and CD8+ T cells

- Peptide transfer via gap junctions (but more in direct priming)

- Expression of cell death signals enhances cross-presenation

- CLEC9A a necrotic cell detector

- selectively expressed by CD8+ and plasmacytoid DCs

Who is priming?

- Cross-priming appears to be dependant on CD8+ CD103+ DCs

- CD8 features: optimizing endolysosome pH, CLEC9A regulated cross-

priming

- CD103+ DCs: migrating subset, transport antigen from periphery to LN

- But in humans?

- maybe BDCA3+ DC similar to CD8+ DC in mouse

-pAPC „Wannabes“ capable of cross-priming:

-pDCs, IFN producing killer DCs, neutrophils (but not in significant quantities?)

Some “practical advice”

- Cross-priming is optimized by expressing long-lived antiges

- extended peptide have increased immunogenicity because of resistance to

protease destruction

- advances in material science offer great promise for polypeptide-based

vaccines: Immunigenicity is increased when delivering antigen and TLR-

activating substances in the same particle

Conclusion

Still a lot to do in science before we really understand

cross-priming based vaccine strategiesThank you for your attention! Questions ???