Allergic asthma is a chronic inflammatory disease of the lung that is continuously exposed to inhaled external materials, including allergens. Th2 cells, major players in the pathology of allergic lung inflammatory disease, accumulated in the bronchoalveolar lavage fluid (BALF) of allergic asthma patients (16). In addition, many studies have highlighted the memory responses of Th2 cells in the pulmonary system in experimental animal models and in asthmatic patients (9, 17–21). These studies provide clues that allergen-specific memory Th2 cells are present in the lungs of asthmatic patients. However, the characteristics of memory Th2 cells have directly not been analyzed for their lifespan and migratory capacity until recently. This was probably due to the proposal that the lung does not provide favorable microenvironments for the survival of memory T cells (22).

Previously, our group employed TCR-transgenic mice and measured the longevity of allergen-specific memory CD4 T cells. We found that these cells survived for over 70 days in the murine lung and airways suffering from allergic inflammation (23). Moreover, it was discovered that allergen-specific memory CD4 T cells showed residency in these tissues and induced rapid and enhanced allergic lung inflammation upon allergen re-exposure. Other groups have suggested that resident memory T (T_RM) cells in the lung are reactivated by allergens in situ and have transcriptional characteristics distinct from those of circulating memory Th2 cells (17, 18, 24). In human asthmatics, allergen-specific CD4 T cells were discovered in BALF after segmental allergen challenge, and these cells mediated allergic lung inflammation by providing type 2 cytokines and eosinophil recruitment (6, 9, 25). Additionally, the microbiota in the upper airways of humans was correlated with the development of adult asthma (26). Contrary to the original proposal, these studies support the notion that allergic lungs provide favorable microenvironments for the homeostasis of allergen-specific memory CD4 T cells.

Recently, it has also been shown that IL-17 producing cells participate in inducing and maintaining allergic asthma. These IL-17-producing memory CD4 T cells were reported to develop from allergen-specific memory Th2 cells after stimulation by proinflammatory cytokines, and to aggravate allergic asthma upon allergen re-exposure in mice and humans (27). Moreover, dual-positive Th2/Th17 cells differentiated from Th2 cells correlated with asthma severity and decreased responsiveness to dexamethasone in the BALF of asthmatic patients (28). These results may indicate that allergen-specific memory CD4 T cells, particularly Th2 cells, mediate disease relapses and aggravation, including steroid unresponsiveness in the lung.

Allergic skin diseases, such as AD and atopic eczema, induced by protein allergens or chemicals, are multifactorial and complex diseases (29). Similar to asthma, several reports have raised a point that these allergic skin diseases are also considered to be initiated and maintained by CD4 T cells (30–33). Upon allergic stimulations, CD4 T cells were shown to migrate massively into the epidermis of itchy sites and induce type 2 immune responses to mediate allergic skin diseases (34, 35). When allergic eczema patients were rechallenged with allergens, the numbers of allergen-reactive Th2 cells increased, mainly due to the proliferation of these cells in the skin lesions (36). Another study using AD patients presented that allergen-specific Th2 cells persisted in the skin for more than four years (37).

In the case of allergic contact dermatitis and contact hypersensitivity, hapten-specific CD4 T_RM cells accumulated even after the skin has healed (38). Further, these cells expanded in the dermis and were sufficient to mediate skin inflammation after re-exposure to the same hapten. Thus, in this type of allergic disease, skin-resident allergen-specific memory CD4 T cells are crucial for mediating local skin inflammation. Altogether, allergen-specific memory CD4 T cells steer the recurrence and exacerbation of allergic inflammation through their persistence and reactivation in the skin.

FA triggers diverse symptoms by mediating type 2 inflammation in various tissues, including the cutaneous and respiratory systems, as well as the gastrointestinal system. In underlying pathologic mechanisms of FA, allergen-specific IgE and Th2 cells are considered important mediators (39–42). In accordance with the development of research tools, recent studies have indicated that allergen-specific CD4 T cells, in particular, IL-13-producing follicular helper T cells, play a role in the production of high affinity IgE rather than Th2 effector cells (43). These findings highlight that allergen-specific CD4 T cells are also involved in the pathology of FA.

Another important aspect of FA is the breakdown of oral tolerance. Oral tolerance to food antigens is mainly maintained by antigen-specific regulatory T (Treg) cells (39, 44). The activation of STAT6 in these Treg cells stimulated by IL-4 reprogrammed and converted them into a Th2-like phenotype, resulting in an imbalance in oral tolerance ( Figure 1B ) (45). Recently, a greater proportion of activated Tregs and memory-like Treg cells were observed in peripheral blood mononuclear cells (PBMCs) of peanut-allergic patients compared to non-allergic controls (46). Since severe manifestations, such as anaphylaxis, are induced after re-exposure to food antigens, it was speculated that food allergen-specific memory CD4 T cells are present in the gastrointestinal system (47). Although the presence and characteristics of allergen-specific memory CD4 T cells in the gut are yet to be defined, these diseases appear to represent memory responses to food allergens.

There have been many attempts to identify allergen-specific memory CD4 T cells regarding to their functions or disease severities in allergic disorders. Among the markers used to define the populations, cytokine or chemokine receptors expressed on CD4 T cells have well been elucidated as characteristics of allergen-specific memory CD4 T cells and Treg cells that mediate their recruitment and regulate their functions in the tissue ( Figure 1 ). These receptors include C-C chemokine receptor 4 (CCR4), a chemoattractant receptor-homologous molecule expressed on Th2 (CRTH2), C-C chemokine receptor type 8 (CCR8), and C-X-C Motif Chemokine Receptor 6 (CXCR6).

OX40L (CD252), a co-stimulator provided by DCs or IgE-activated mast cells, stimulates allergen-specific CD4 T cells to promote their clonal expansion and survival during the primary response and induces the development of allergen-specific memory CD4 T cells (69–72). Consistent with this, OX40 expressing memory CD4 T cells co-localized with OX40L⁺ DCs or OX40L⁺ mast cells to enhance allergic inflammation in the lung and skin upon re-exposure to allergens or epithelial cell-derived cytokines (73–75). Moreover, a blockade of OX40L induced the tolerogenic state of allergen-specific memory CD4 T cells, resulting in the reduced severity of airway inflammation (75). Altogether, OX40L derived from immune cells, including DCs and mast cells, is crucial for the development, maintenance, and reactivation of allergen-specific memory CD4 T cells to exacerbate allergic diseases.

Local tissue-derived cytokines, particularly epithelial cell-derived cytokines called alarmins, such as TSLP, IL-33, and IL-25, are positively correlated with the severity of allergic diseases and are crucial for inducing Th2 polarization (76–79). Furthermore, recent studies have shown that these epithelium-derived signals influence the survival and reactivation of memory CD4 T cells (80–82).

Epigenetic modifications of chromatin structure including DNA methylation and post-translational modifications of histones are well known to determine and maintain the differentiation of cells for regulating the gene expression patterns (83). Moreover, IL-4 in memory Th2 cells is rapidly expressed by this type of epigenetic modification upon antigen re-stimulation (84). Thus, epigenetic changes are crucial strategy for enhancing the function of memory Th2 cells. These alarmins have been proposed to mediate chromatin modification of allergen-specific memory CD4 T cells resulting in the enhancement of type 2 cytokine expressions. For example, TSLP stably programmed the effector state of memory Th2 cells by hyperacetylation within Th2 cytokine locus (81). Additionally, allergen-specific memory T cells expressing ST2 produced high levels of IL-5 by selective remodeling of chromatin structure at the Il5 locus with a challenge of IL-33 without allergen (85).

Recent research reported another role of IL-33 in allergic response. ST2^hi memory CD4 T cells stimulated by IL-33 produced epidermal growth factors, particularly amphiregulin. This growth factor reprogrammed eosinophils toward an inflammatory state and then induced fibrosis of nasal polyps in allergic rhinitis (86).

Although individual alarmins have been intensively studied, these cytokines are also known to be released and to cooperate in the same organ to develop a memory Th2 response. DCs activated by TSLP enhanced the expression of IL-17RB on memory Th2 cells by providing OX40L. Finally, memory Th2 cells, which were stimulated by IL-25, upregulated transcription factors including GATA-3, c-Maf, and Jun B, and type 2 cytokines in the absence of TCR triggering (87). Altogether, these results imply that tissue-derived cytokines have many aspects to reactivate allergen-specific memory CD4 T cells for the pathology of allergic diseases.

Increasing efforts to identify homeostatic microenvironments for the formation, survival, and maintenance of allergen-specific memory CD4 T cells have led to a better understanding of the mechanisms underlying allergic disease relapses.

First, it was reported that DCs and IL-2 signalings, which are known to be critical to the activation and proliferation of naïve T cells, contributed to the formation of memory Th2 cells. In a mouse model of allergic asthma, IL-2 signalings provided in the allergic lung microenvironments importantly facilitate the early residency of memory Th2 cells (88). DCs, particularly TSLP-activated DCs, also induced the homeostatic proliferation of allergen-specific central memory Th2 cells to maintain the pool of these cells without antigens (72). Thus, these findings suggest that IL-2- and DC-mediated signalings are crucial for the homeostasis of allergen-specific memory CD4 T cells.

Second, IL-7 and IL-15 are well documented to be important for the survival and homeostatic proliferation of memory CD8 T cells (89). The roles of these cytokines in the maintenance of memory CD4 T cells have also been studied. Between these two cytokines, IL-7 enhanced the survival of memory Th2 cells by increasing the expression of anti-apoptotic protein Bcl-2 (90). This cytokine, produced by Thy1⁺ lymphatic endothelial cells, provided a survival environment for allergen-specific memory Th2 cells in the inducible bronchus-associated lymphoid tissue of the lung, which is formed after allergic lung inflammations in humans and mice (90). IL-7 is also crucial for the development of memory CD4 T cells by mediating the transition of effector T cells into memory T cells (91). In the lung and airways suffered from allergic inflammation, the generation of allergen-specific memory CD4 T cells was affected by IL-7Rα-mediated signals (23). Moreover, in a skin hypersensitivity model, hair follicle-derived IL-7 was required to maintain memory CD4 T_RM cells (92). Accordingly, it has been suggested that IL-7 plays an important role in the homeostasis of allergen-specific memory CD4 T cells in barrier tissues.

Our bodies have evolved immune homeostasis mechanisms that need to decide between protection against pathogens and tolerance to innocuous substances, such as food, commensal bacteria, and inhaled environmental particles (93, 94). Among these mechanisms, it has extensively examined that Treg cells play a crucial role in preventing the development and aggravation of hypersensitivity against harmless environmental substances (95). The underlying mechanisms include the development of Treg cells in the thymus by TGF-β signaling, which mediates the suppressive functions of these cells in certain peripheral tissues (96, 97). In an experimental model of FA, TGF-β1-deficient allergen-specific Treg cells did not develop into oral tolerance-promoting RORγt⁺ Treg cells, resulting in an increased incidence of FA. Furthermore, the regulation of oral tolerance mediated by RORγt⁺ Tregs was affected by microbiota-derived signals (98). These findings suggest that extrinsic factors contributing to immune tolerance by stimulating allergen-specific CD4 T cells are required to modulate allergic disorders.