The benefits of diversity: heterogenous DC populations allow for both immunity and tolerance.

The immune system must simultaneously mount a response against foreign antigens while tolerating self. How this happens is still unclear as many mechanisms of immune tolerance are antigen non-specific. Antigen specific immune cells called T-cells must first bind to Immunogenic Dendritic Cells (iDCs) before activating and proliferating. These iDCs present both self and foreign antigens during infection, so it is unclear how the immune response can be limited to primarily foreign reactive T-cells. Regulatory T-cells (Tregs) are known to play a key role in self-tolerance. Although they are antigen specific, they also act in an antigen non-specific manner by competing for space and growth factors as well as modifying DC behavior to help kill or deactivate other T-cells. In prior models, the lack of antigen specific control has made simultaneous foreign-immunity and self-tolerance extremely unlikely. We include a heterogeneous DC population, in which different DCs present antigens at different levels. In addition, we include Tolerogenic DC (tDCs) which can delete self-reactive T-cells under normal physiological conditions. We compare different mathematical models of immune tolerance with and without Tregs and heterogenous antigen presentation. For each model, we compute the final number of foreign-reactive and self-reactive T-cells, under a variety of different situations. We find that even if iDCs present more self-antigen than foreign antigen, the immune response will be primarily foreign-reactive as long as there is sufficient presentation of self-antigen on tDCs. Tregs are required primarily for rare or cryptic self-antigens that do not appear frequently on tDCs. We also find that Tregs can only be effective when we include heterogenous antigen presentation, as this allows Tregs and T-cells of the same antigen-specificity to colocalize to the same set of DCs. Tregs better aid immune tolerance when they can both compete for space and growth factors and directly eliminate other T-cells. Our results show the importance of the structure of the DC population in immune tolerance as well as the relative contribution of different cellular mechanisms.