Identifying cancer and pathogen-specific epitopes or TCRs may sound intuitive, but it is a futile approach. Diversity of T cell or B cell clones guarantees that the adaptive immune system will always have relevant clones to detect cancer or pathogen.
Epitopes have no meaning attached to them with one exception. It is when the said epitope is self. Each body will have different sets of self-epitopes. Every self-epitopes relevant for host's survival are encoded in the thymus, and thymic Tregs are trained to prevent any T cell activity against those epitopes in the periphery. This is called tolerance, and it is antigen[epitope]-specific.
Then what prevents effective responses to cancers or pathogens? It is commonly but mistakenly believed that Tregs prevent effective T or B cell responses to cancers or pathogens. But Tregs only prevent anti-self response, and it is epitope-specific action. So, by definition, if Tregs do their job as required, we cannot blame them. But it has nothing to do with cancer or pathogens, which obviously have other epitopes different from self, we call nonself. So, if cancer cells or pathogens express nonself epitopes that are always detected by adaptive immune system, why not everyone can fight it off effectively?
This is because T cells themselves prevent it. Yes, T cells, not Tregs, prevent effective response to cancers or pathogens in certain conditions. What are those conditions? These are condition when polarized T helper cells prevent other T cells functions. Polarization is a pathological state. A Polarized T cell's effect on other T cells is epitope non-specific, meaning, a polarized T helper cell specific to cancer or pathogen nonself epitope A will prevent T cells specific to epitope B, C, D, E, F, etc., to function properly. It is exactly Treg's job to shut down those polarized T helper cells to allow other T cells to manifest their functions and get rid of either cancer or pathogen. And Treg do it, as we already said, epitope-specific manner.
For this reason, it is not so important to identify any cancer or pathogen-specific nonself epitope, but rather to identify an epitope that could activate polarized T helper cells.
To make things even more complicated, one may ask if Tregs are self-specific and act epitope-specific manner, how can Tregs shut down polarized T helper cells that are nonself-specific? It is possible because Tregs are cross-reactive and can inhibit only those polarized T helper cells which share TCR specificity with Tregs.
In other words, control of self-tolerance and control of effective anti-nonself response are one and the same.
These are 3 papers that together provide a full discussion related to the SPIRAL model we have developed to explain how Tregs work within an adaptive immune system:
Concurrent cross-reactivity of microbiota-derived epitopes to both self and pathogens may underlie the "Hygiene hypothesis"
Could cross-reactivity rescue Foxp3+ regulatory T cell precursors from thymic deletion?
Microbiota-Specific Foxp3+ Regulatory T Cells Could Control Pathological T Helper Responses
