Heterogeneity in the initiation, development and function of type 2 immunity

Abstract

Type 2 immune responses operate under varying conditions in distinct tissue environments and are crucial for protection against helminth infections and for the maintenance of tissue homeostasis. Here we explore how different layers of heterogeneity influence type 2 immunity. Distinct insults, such as allergens or infections, can induce type 2 immune responses through diverse mechanisms, and this can have heterogeneous consequences, ranging from acute or chronic inflammation to deficits in immune regulation and tissue repair. Technological advances have provided new insights into the molecular heterogeneity of different developmental lineages of type 2 immune cells. Genetic and environmental heterogeneity also contributes to the varying magnitude and quality of the type 2 immune response during infection, which is an important determinant of the balance between pathology and disease resolution. Hence, understanding the mechanisms underlying the heterogeneity of type 2 immune responses between individuals and between different tissues will be crucial for treating diseases in which type 2 immunity is an important component.

Fig. 1 |. Initiation of the type 2 immune response.

Disruption of the epithelial cell barrier or damage to visceral tissues triggers cell damage or death, including programmed cell death signalling pathways, specific cell–tissue matrix interactions, and subsequent release of damage-associated molecular patterns (DAMPs) and the associated alarmins. In the absence of microbial pathogen-associated molecular patterns, which can otherwise promote a type 1 response, these signals then drive the activation of innate immune cells, including myeloid cells (neutrophils, eosinophils, basophils, macrophages, monocytes and dendritic cells) and group 2 innate lymphoid cells (ILC2s). All of these innate immune cells are activated through similar signalling pathways, such as IL-4 receptor signalling, resulting in shared phenotypes, including the expression of type 2 cytokines. However, distinct expression of specific genes and proteins may also occur simultaneously, depending on the specific immune cell lineage and the tissue microenvironment. IFN, interferon; RELMα, resistin-like molecule-α; TSLP, thymic stromal lymphopoietin.

Fig. 2 |. Effects of type 2 immunity.

The type 2 immune response mediates host protection against helminths, promoting resistance and various tolerance mechanisms, including mitigation of tissue damage through control of harmful inflammation and through directly enhancing tissue repair. These processes can have multiple effects on the host physiology, in some cases promoting homeostasis, but also potentially causing considerable tissue damage. Type 2 immunity can promote metabolic homeostasis, wound healing and control of various autoinflammatory conditions, ranging from type 1 and type 2 diabetes to certain types of inflammatory bowel disease. It can also cause immediate hypersensitivity, allergic reactions and harmful sterile inflammation, with chronic type 2 responses contributing to tissue-damaging fibrosis. BTK, Bruton’s tyrosine kinase; RELMα, resistin-like molecule-α; SYK, spleen tyrosine kinase.

Fig. 3 |. Factors influencing the heterogeneity of type 2 immunity.

The type 2 immune response shows considerable heterogeneity, and the causal factors that contribute to the marked differences in responses have as yet been little studied. The factors that may influence this variability are numerous. The specific stimulus can greatly affect the response: stimuli range from helminths, which produce excretory/secretory proteins and trigger the release of endogenous danger signals through tissue damage, to allergens and sterile microparticles. The microbiota, including commensal bacteria as well as other associated organisms, such as viruses and fungi, may also be critical. The specific tissue microenvironment in which the response occurs and the associated tissue matrix–cell interactions may also influence the course of the response. Previous exposure to pathogens or other insults, including allergens and pollutants, may further influence how the current response develops, with epigenetic regulation likely playing a major role in trained innate immunity and memory-adaptive responses. In this context, ongoing changes in metabolic activity may also influence the development of subsequent responses. Death signalling pathways are now recognized as playing a critical role in shaping this response. Finally, genetics can also play an essential role. In an actual response, all of these factors interact, culminating in multiple signals that drive heterogeneity in the initiation, nature, magnitude and chronicity of the type 2 immune response.

Fig. 4 |. Interindividual heterogeneity of type 2 immune responses.

a | There is considerable variation in the ability of individuals to mount type 2 immune responses. Where most individuals can mount an optimal response to expel most of the helminth parasites they encounter while tolerating a few parasites to maintain an asymptomatic helminth infection, some individuals with a very weak type 2 response will become ‘superinfected’ and have very heavy worm burdens, resulting in severe pathology. Individuals who have weak type 2 responses might also be more susceptible to metabolic conditions such as obesity and atherosclerosis. In contrast, individuals that can mount very strong type 2 immune responses may be more resistant to helminth infections but are more susceptible to immune-driven pathology. Such individuals may also be more susceptible to type 2-driven atopic diseases, such as asthma and atopic dermatitis. This variation in the strength of the type 2 immune response could be driven by a combination of genetic and environmental effects. b | We hypothesize that the environment is the most important driver of variation in the number and composition of cells that are present in the individual, as previous exposure to infection and the microbiota may alter the abundance of the immune cell population in the individual. Perhaps the genetic composition of the individual is a more important determinant of the amount of cytokine that each of the immune cells can produce in response to stimulation. Hence, a combination of environment and genetic variables will determine the overall strength of the type 2 immune response.