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

- We describe a mathematical model of immune tolerance, in which there is simultaneously a T-cell response to a foreign antigen and tolerance of a self-antigen.
- We find that either Tolerogenic Dendritic Cells (DCs) or Regulatory T-cells (Tregs) can induce tolerance. Tregs require heterogenous presentation of antigen by DCs in order to function this way.
- We test the robustness of the model across different antigen types and find that Tolerogenic DC are more useful for tolerance to ubiquitous antigens, whereas Tregs are useful for cryptic antigens.
- We also investigate the difference in behaviour between Tregs that can induce T-cell anergy or death versus Tregs that only compete for space on DCs and for growth factors. We find that Tregs perform most robustly when they can do both.
- We develop a modeling framework with great flexiility, that can be used to model a heterogenous DC population interaction with many populations of T-cells.

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.