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Synopsis Immunopathology, or the harm caused to an organism’s own tissues during the activation of its immune system, carries substantial costs. Moreover, avoiding this self-harm may be an important mechanism underlying tolerance of infection, helping to reducing fitness costs without necessarily clearing parasites. Despite the apparent benefits of minimizing immunopathology, such damage persists across a range of host species. Prior work has explored a trade-off with resistance during a single infection as a potential driver of this persistence, with some collateral damage being unavoidable when killing parasites. Here, we present an additional trade-off that could favor the continued presence of immunopathology: robust immune responses during initial infection (e.g., innate immunity in vertebrates) can induce stronger memory (adaptive immunity), offering protection from future infections. We explore this possibility in an adaptive dynamics framework, using theoretical models parameterized from an ecologically relevant host-parasite system, house finches (Haemorhous mexicanus) infected with the bacterial pathogen, Mycoplasma gallisepticum. We find that some degree of immunopathology is often favored when immunopathology during first infection either reduces susceptibility to or enhances recovery from second infection. Further, interactions among factors like transmission rate, recovery rate, background mortality, and pathogen virulence also shape these evolutionary dynamics. Most notably, the evolutionary stability of investment in immunopathology is highly dependent upon the mechanism by which hosts achieve secondary protection (susceptibility vs. recovery), with the potential for abrupt evolutionary shifts between high and low investment under certain conditions. These results highlight the potential for immune memory to play an important role in the evolutionary persistence of immunopathology and the need for future empirical research to reveal the links between immunopathology during initial infections and longer-term immune protection. 

Immune systems pose fascinating puzzles for evolutionary biologists. They feature some of the most polymorphic genes and reflect the strongest natural selection known. Evolution of immune systems plays a key role in host–parasite interactions, speciation, and eco-evolutionary dynamics that have community- and ecosystem-wide consequences. Conversely, evolutionary perspectives enrich our understanding of immunology, revealing macroevolutionary origins of key immune traits, their function in wild populations as opposed to sterile lab settings, and trade-offs that constrain immune adaptation. Here, we review key themes in the fast-growing interdisciplinary field of evolutionary immunology, focusing on multicellular animals. We describe macroevolution of immune functions, evidence of contemporary selection on immune genes, and the underlying theory seeking to explain this selection at multiple biological scales. We identify major open questions and opportunities in the field today. Foremost among these is the challenge of accurately and appropriately measuring relevant immune traits in wild and nonmodel organisms, which is necessary to understand their evolution in natural settings. A second challenge is to describe how diverse communities of symbionts impose selection on the highly multivariate and pleiotropic immune system. 

Inbred mice used for biomedical research display an underdeveloped immune system compared with adult humans, which is attributed in part to the artificial laboratory environment. Despite representing a central component of adaptive immunity, the impact of the laboratory environment on the B cell compartment has not been investigated in detail. Here, we performed an in-depth examination of B cells following rewilding, the controlled release of inbred laboratory mice into an outdoor enclosure. In rewilded mice, we observed B cells in circulation with increased signs of maturation, alongside heightened germinal center responses within secondary lymphoid organs. Rewilding also expanded B cells in the gut, which was accompanied by elevated systemic levels of immunoglobulin G (IgG) and IgM antibodies reactive to the microbiota. Our findings indicate that exposing laboratory mice to a more natural environment enhances B cell development to better reflect the immune system of free-living mammals. 

Infection duration affects individual host fitness and between-host transmission. Whether an infection is cleared or becomes chronic depends on the complex interaction between host immune responses and parasite growth. Empirical and theoretical studies have suggested that there are critical thresholds of parasite dose that can determine clearance versus chronicity, driven by the ability of the parasite to manipulate host immunity. However, the mammalian immune response is characterized by strong positive and negative feedback loops that could generate duration thresholds even in the absence of direct immunomodulation. Here, we derive and analyse a simple model for the interaction between T-cell subpopulations and parasite growth. We show that whether an infection is cleared or not is very sensitive to the initial immune state, parasite dose and strength of immunological feedbacks. In particular, chronic infections are possible even when parasites provoke a strong and effective immune response and lack any ability to immunomodulate. Our findings indicate that the initial immune state, which often goes unmeasured in empirical studies, is a critical determinant of infection duration. This work also has implications for epidemiological models, as it implies that infection duration will be highly variable among individuals, and dependent on each individual’s infection history.