This essential feature of T-cell help, a feature

that ensures help is not given to just any cell (i.e. it increases specificity), is likely to underlie the otherwise paradoxical finding that T-cell helpers to adenovirus do not provide effective helper epitopes for the anti-GUCY2C CD8+ T-cell response. As Snook et al. [18] suggest, the timing of adenoviral antigen and GUCY2C tumor antigen expression is distinct and hence presentation of these antigens will not be linked but rather be presented by different antigen-presenting cells. In terms of the mechanism of tumor elimination, this study supports a central role for CD8+ T cells that have received adequate T-cell help.

CD4+ T cells have also been shown to have a potent PD98059 chemical structure capacity to eliminate tumor cells through perforin/granzyme B or macrophage induction [20] and they can cause substantial collateral tissue damage [21], a capacity that may be of utility in preventing immune escape of malignant cells that have downregulated tumor antigen expression. Although well known for their ability to help CD8+ T cells and B cells, CD4+ T cells can help each other in their activation and differentiation as seen in systems where addition of a foreign helper epitope (e.g. OVA) linked to a second Y-27632 order antigen (e.g. HEL) increases the CD4 response to the second antigen [22, 23]. Nevertheless, in the studies of Snook et al. CD4+ T-cell tolerance to GUCY2C appears to be robust and not easily overcome by additional CD4+ T-cell help. However, should there exist cases where tolerance in CD4+ T cells to a given self/tumor antigen is not complete, provision of foreign helper epitopes could promote their activation, allowing these CD4+ T cells to participate in tumor elimination independent of CD8+ T cells and B cells. Whether cancer vaccines should focus on the promotion of MHC class I- or MHC class II-restricted effector Ceramide glucosyltransferase cells is not necessarily obvious and will require careful dissection of mechanism of

tumor killing generated by the most efficacious vaccines. The benefit of CD8+ T-cell responses is that they may be more self-limiting [17], causing less autoimmune damage. This, however, comes at the potential cost of allowing tumor variants to escape the effector mechanism of destruction. Will provision of foreign helper determinants to cancer vaccines be expected to universally augment tumor immunity? The answer is likely to be no, as exemplified in a study where higher doses of a plasmid encoding a foreign helper epitope in a DNA cancer vaccine reduced vaccine efficacy and survival post tumor challenge [10]. This is consistent with the current study by Snook et al.