Intercellular Communication in the Adaptive Immune System: A Systems Approach

Nicole Pagane, Massachusetts Institute of Technology

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The adaptive immune system neutralizes threats by recognizing and responding to different antigens. To avoid autoimmune diseases, the immune system must learn to discriminate between self and non-self, and this discrimination was thought to be primarily established at the molecular scale. During the development of immune cells with antigen specific receptors, cells with receptors that recognize self antigens too strongly are eliminated. However, recent work highlights that self discrimination is additionally regulated at the local tissue scale through an intercellular feedback circuit that prunes self-reactive immune cells.

This circuit involves an antigen presenting cell (APC) that presents antigens to conventional T cells (Tconv) and T regulatory cells (Treg), where Tconvs are typically non-self antigen specialists that fight off infections and Tregs are self-antigen specialists that regulate Tconv responses. If a Tconv recognizes antigen on an APC, it will start to mount an immune response by secreting the diffusible signal IL-2. Nearby Tregs, activated by self antigen on the APC, competitively absorb IL-2 from the Tconv and remove immune stimulatory molecules from the APC. Thus, this competition between Tconvs and Tregs regulates immune activation in lymph nodes. Tconvs activated by foreign antigens typically escape this regulation, while self-activated Tconvs tend to be suppressed.

To explore this dynamic competition, we simulate the intercellular system with different levels of abstraction. First, we construct a minimal mathematical representation of the circuit to determine the local sensitivity of parameters in order to predict different behavior regimes of the system. Second, we develop a more sensible kinetic model that incorporates both intracellular and intercellular dynamics to determine the global sensitivity of these more resolved parameters. Lastly, we work towards a reaction-diffusion system, where the diffusible signals that enable intercellular communication form gradients, to gain further insights into the spatial and temporal regulation of immune activation.

Abstract Author(s): Nicole Pagane, Harikesh Wong