Cross-presentaion, cross-priming

I have recently found some interesting information in relation two questions that have been ringing in my mind for a while and I’ll post each separately to avoid a long post:

First Question: Isn’t it likely that the Dendritic cell (DC) will be killed by CTL when it cross-presents antigens with MHC classI?

Having read through few articles on the subject, here is the scenario I would put:

· If an APC is virally infected (ie with viral replication inside it), then one would expect it to present some of the virally derived antigens in association with MHCI and I suppose that if the CTL delivers an apoptotic signal to the APC after Ag recognition then this would be beneficial.

· In case of tumors not invading into the APC’s or viruses that do not infect the APC’s (ie. extracellular antigens) then only through cross-presentation would it possible to excite a CTL response (ie dendritic cells (DC) would ingest this extracellular antigen, process it and present it in association with MHC I). So, this is also cross-priming. The question becomes: wouldn’t this be detrimental as CTL activation would mean death to the DC? Here is the issue: Only certain subsets of DC in the lymph nodes are capable of cross-presentation (these are well characterized by surface markers in mice but not in humans yet) and I would quote this from a recent review paper published in nature immunology reviews (1):” During a systemic infection, all DCs might be killed if they all could cross-present. Although DCs possess mechanisms to avoid CTL-mediated killing to some degree, it is clear that cross-presenting DCs can be effectively killed during viral infections. However, this killing does not seem to affect the ensuing immune response as CTLs need less than one day of antigen presentation by DCs for activation and a little longer for developing cytolytic functionality, and they can then carry out their tasks without continual stimulation, at least for some days” (1)

· Now the question becomes: how then could a DC activate CD4-helper T cells in case of an intracellularly derived antigen which is usually presented with class I MHC but not class II ? I just found talk about “Autophagy pathway” in DC’s in which intracellular antigens can be taken into autophagosomes, degraded in lysosomes and presented in association with MHC class II (2).

So it seems that within the DC’s, the pathways of Ag-presentation in association with MHC classes I or II complement each other as needed.

Question: Relevance and application of cross-priming??

I hope you can see that it is of value to combat viral infections in which DC’s are not infected and also to combat tumors. There is beautiful discussion in the paper of Kurtis et al. about the application of this in cancer therapy: for example, not removing draining lymph nodes even when negative for any tumor spread (contrary to current strategies), and the use of the tumor as its’ own vaccine.

(1) Kurtis C, Robinson BWS and Knolle PA. Cross-priming in health and disease. Nature reviews/ immunology. June 2010; 10: 403-414.

(2) Li Y, Wang L, Pang P, Twitty C, Fox BA, Aung,S, UrbaWJ and Hu H. Cross-presentation of tumor associated antigens through tumor-derived autophagosomes. Autophagy. 2009; 5(4): 576-577.