Optimal evolutionary decision-making to store immune memory

Abstract

<jats:p>The adaptive immune system in vertebrates consists of highly diverse immune receptors to mount specific responses against a multitude of pathogens. A central feature of the adaptive immune system is the ability to form a memory to act more efficiently in future encounters with similar pathogens. However, memory formation especially in B-cells is one of the least understood cell fate decisions in the immune system. Here, we present a framework to characterize optimal strategies to store memory in order to maximize the utility of immune response to counter evolving pathogens throughout an organism’s lifetime. To do so, we have incorporated the kinetics and energetics of memory response as ingredients of non-equilibrium decision-making between an adaptive exploration to mount a specific and novel response or exploitation of existing memory that can be activated rapidly yet with a reduced specificity against evolved pathogens. To achieve a long-term benefit for the host, we show that memory generation should be actively regulated and dependent on immune receptors’ affinity, with a preference for cross-reactive receptors with a moderate affinity against pathogens as opposed to high affinity receptors— a recipe that is consistent with recent experimental findings [1, 2]. Moreover, we show that the specificity of memory should depend on the organism’s lifespan, and shorter-lived organisms with fewer pathogenic encounters throughout their lifetime should store more cross-reactive memory. Overall, our framework provides a baseline to gauge the efficacy of immune memory formation in light of an organism’s coevolutionary history with pathogens.</jats:p>

Affinity maturation for an optimal balance between long-term immune coverage and short-term resource constraints

“…Previous work developed models of repertoire organization as a constrained optimization problem where the expected future harm of infection, or an ad hoc utility function, is minimized [30,41,42,54]. In Ref.…”

“…Our work addresses these challenges by proposing a framework of discrete-time decision process to describe the optimal remodeling of the B-cell repertoire following immunization, through a combination of affinity maturation and backboosting. While similar to [30], our approach retains the minimal amount of mechanistic details and focuses on questions of repertoire remodeling, dynamics, and structure. The specific choices of the cost functions were driven by simplicity, while still retaining the ability to display emergent behaviour.…”

“…Despite long-lasting efforts to describe the co-evolution of pathogens and hosts immune systems [25][26][27][28][29], and recent theoretical work on optimal schemes for using and storing memory in the presence of evolving pathogens [30], few theoretical works have described how the B-cell memory repertoire is modified by successive immunization challenges. Early observations in humans [31] have shown that sequential exposure to antigenically drifted influenza strains was more likely to induce an immune response strongly directed towards the first strain the patients were exposed to [32].…”

Learning and organization of memory for evolving patterns

“…On the other hand, the adaptive immune system, which encounters evolving pathogens, allocates distinct immune cells (i.e., compartments) to store a memory for different types of pathogens (e.g. different variants of influenza or HIV)-a strategy that resembles that of the 1-to-1 specialized networks [5,[27][28][29][30][31][32]. Our results suggest that pathogenic evolution may be one of the reasons for the immune system to encode a specialized memory, as opposed to the distributed memory used in the olfactory system.…”

“…Immune cells activated in response to a pathogen can differentiate into memory cells, which are long lived and can more efficiently respond upon reinfections. As in most molecular interactions, immune-pathogen recognition is cross-reactive, which would allow memory receptors to recognize slightly evolved forms of the pathogen [5,[27][28][29][30][31][32]. Nonetheless, unlike the distributed memory in the olfactory cortex, the receptors encoding immune memory are focused and can only interact with pathogens with limited evolutionary divergence from the primary infection, in response to which memory was originally generated [5].…”