Open access peer-reviewed chapter - ONLINE FIRST
Abstract
The skin is the largest defense organ and immune organ. Establishing immune memory in the skin is a key component of the acquired immune response. The skin harbors several subpopulations of memory T cells in the skin, including tissue resident memory T cells (TRMs). TRMs have a unique transcriptional profile, with the most significant features of long-term survival (lifespan) and long-term residence in skin lesions. Under physiological conditions, TRMs can respond quickly to the challenge of pathogen infection. However, increasing evidence supports their role in the recurrence of chronic inflammatory skin diseases under uncontrolled conditions. Elucidating the characteristics of skin TRMs will help to provide promising strategies for reducing the frequency and severity of skin inflammation recurrence. In this chapter, we plan to discuss the latest consensus on the biology of TRMs, and share our views on the roles of TRMs in the recurrence of inflammatory skin diseases.
Keywords
- tissue-resident memory T cells
- skin barrier
- immunological memory
- disease recurrence
- skin inflammation
- TRMs
1. Introduction
The body is covered by barrier tissues, such as the skin. Pathogens stimulate dendritic cells (DCs) below the skin through these barrier tissues. DC captures incoming antigen(s) and then migrates to local draining lymph nodes, presenting the antigen to naive T cells. Once activated, naive T cells proliferate and transform into effector T cells, migrating to the B cell region or inflammatory site. A small fraction of activated T cells differentiates into memory T cell precursors. Based on effector function, proliferation ability, and migration potential, these precursor memory cells ultimately develop into distinct subgroups of memory T cells, including tissue resident memory T cells (TRMs) [1].
TRMs are one of the main executors of immunological memory. They do not express CD62L or CCR7, but constantly express receptors such as CD69, CD103, and CD49a, exhibiting unique characteristics of long-term survival and low migration in peripheral tissues. The specific expression pattern of these receptors is largely determined by the microenvironment of peripheral tissue in which TRMs are located. TRMs are a specific subgroup of memory T cells, and possess a unique transcriptional profile different from central memory T cells or effector memory T cells [2].
Research has demonstrated that skin TRMs can significantly over-express genes related to the acquisition of free fatty acid metabolism, thereby further enhancing their ability to utilize fatty acid oxidation [3], which suggests their outstanding ability to adapt to harsh peripheral tissue environments such as glucose depletion. This is one of the important mechanisms of long-term survival in TRMs. Apart from their longevity, low migration in peripheral tissues is also a significant feature of TRMs. Once TRMs reside in peripheral tissues, they will not easily return to the circulating blood due to other stimuli (also exceptions) [4]. On the one hand, TRMs can provide rapid first-line protective immunity when exposed to exogenous antigens again, and on the other hand, they may also play a key role in the recurrence of chronic inflammatory diseases such as psoriasis and fixed drug eruption.
2. Long-term survival in peripheral tissues
Research has shown that in the absence of antigen stimulation, the survival of TRMs in peripheral tissues is mainly regulated by the local microenvironment. These local microenvironmental factors are related to tissue specificity, e.g., in skin tissue, keratinocytes and fibroblasts may play a key role. They undergo significant changes in chronic inflammatory skin damage, and are the main source of IL-7, IL-15, and TGF that may promote T-cell survival, trafficking, and interactions with keratinocytes [5]. It has been demonstrated that hair follicle expression of IL-15 is required for the homeostasis of CD8+ TRMs, and IL-7 for both CD8+ and CD4+ TRMs in the skin [6].
Multiple interrelated intracellular signaling pathways may be involved in the long-term survival of TRMs in peripheral tissues, including JAK/STAT5, PI3K/Akt, and Notch signaling pathways. Research has shown that after the action of IL-7 and/or IL-15, both long-lived memory T cells and short-lived effector T cells can quickly activate the JAK/STAT5 pathway, but the phosphorylation level of STAT5 in the former is much higher than that in the latter [7]. Moreover, sustained high-level STAT5 activation can significantly enhance the expression of anti-apoptotic protein BCL-2 and the survival time of memory T cells [8]. The PI3K/Akt pathway is more strongly activated in long-lived memory precursor T cells than in short-lived effector cells, and inhibition of this pathway can lead to the restricted formation of CD8 + memory T cells. However, further research has found that sustained PI3K/Akt activation does not enhance the survival of CD8 + memory T cells, but rather inhibits the expression of IL-7 and IL-15 receptors, STAT5 phosphorylation, and BCL-2 expression, indicating that the survival of TRMs may depend on the optimized balance of PI3K/Akt signaling [9].
Research has shown that the Notch signaling pathway can affect the survival of CD4 + memory T cells in circulating blood by regulating Akt phosphorylation and glucose uptake. Moreover, subpopulations of CD8 + CD69 + TRMs from various tissues can highly express Notch-1. The inhibition of Notch signaling can affect the expression of specific genes such as CD103, Tmem37, and Acer2 in TRMs [10, 11]. Tmem37 can stabilize calcium ion channels and voltage-gated ion channels; Acer2 can hydrolyze ceramides into sphingosine and free fatty acid. Sphingosine-1-phosphate (S1P) has been shown to promote cell survival [12]. The uptake of exogenous free fatty acid is crucial for the long-term survival of skin TRMs. Knockout of lipid transport molecules of fatty acid binding protein (FABP4 and FABP5) increased in psoriasis lesions can affect the long-term survival of CD8 + TRM cells in the skin [13, 14]. It can be seen that Notch signaling is of great importance to TRMs.
It has been shown that skin CD8+ TRMs upregulate the genes related to lipid uptake and metabolism (e.g., FABP4/5), and utilize mitochondrial fatty acids oxidation (FAO) to support their long-term survival [15]. That is to say, metabolic reprogramming is closely related to the longevity of TRMs. This is actually not limited to resident cells in peripheral lesions, as the immune cell subpopulations in circulating blood are also regulated by different metabolic patterns [16].
3. Long-term residency in peripheral tissues
TRMs can survive for several months (e.g., in the lungs) to several years (e.g., in the skin) in different peripheral tissues. Research has confirmed that the CD69, CD49a, CD103, CCR7, and CCL27-CCR10 axes are closely related to the long-term residence of TRMs in peripheral tissues.
CD69 is a membrane-bound type II C-lectin receptor. Due to its rapid appearance on the surface of the plasma membrane after stimulation, it has been considered as a classic early marker of lymphocyte activation. However, increasing evidence suggests that the role of CD69 in the immune system is far more complex than currently recognized. The main mechanism by which CD69 resides in the periphery of TRMs is to inhibit the expression and function of S1PR1 (sphingosine 1-phosphate acid receptor type 1) on the cell surface. S1PR1 is a downstream target of Kruppel-like factor 2 (KLF2) and mTOR, and involved in T cell migration from peripheral tissue. Research has shown that CD8 + TRMs lack S1PR1 expression, and forced expression of S1PR1 or loss of CD69 can significantly prevent peripheral residence of TRMs [17, 18]. It is now clear that cytokines (including TGF and Type I IFN) that induce the phenotype of TRMs can increase the expression of CD69 and CD49a, and inhibit the KLF2 pathway [19].
CD49a (integrinα1) participating in collagen IV binding is likely to mediate the residence of TRMs in mucosal tissue and the basement membrane zone. Blocking CD49a can reduce the number of TRMs in the mucosal site [20]. CD103 (ITGAE, Integrin alpha E) is enhanced in inflammatory diseases. The binding of CD103 to E-cadherin enhances intercellular interactions and adhesion. Lymph node homing receptor CCR7 is involved in the migration of T cells in peripheral tissues and has a synergistic effect with S1PR1. Therefore, downregulation of CCR7 expression may be another important mechanism for TRMs to reside in peripheral tissues [21]. CCR10 and its ligand CCL27 are highly specific chemokines in skin tissue. Research has shown that CCL27 increases not only during the inflammatory process but also maintains a high level several weeks after allergen attack. Consistent with the increased expression of CCL27, a large number of CD4 + CCR10 + T cells still exist in the skin lesions of allergic contact dermatitis several weeks after clinical recovery, suggesting that the CCL27-CCR10 axis is also an important mechanism for TRM cell retention [22].
4. The plasticity of TRMs
TRMs form a heterogeneous population that provides localized protection against pathogens. They can be further classified by their functional outputs and diversity in phenotypes. These classifications of TRMs are linked to their heterogeneity and plasticity [23]. For example, in the skin, there are both CD69 + CD103 + and CD69 + CD103 - populations, as well as both CD8 + CD49a + and CD8 + CD49a - populations of TRMs. In vitiligo skin lesions, CD8 + CD49a + TRMs produce IFN-γ, perforin, and granzyme B when stimulated with IL-15. On the contrary, CD8 + CD49a- TRMs in psoriatic lesions mainly produce IL-17 cytokines, exacerbating the local inflammation of this skin disease [24].
Important signals for the plasticity of TRMs in multiple tissues include TGF-b, aryl hydrogen receptor (Ahr) ligands, type I IFN, and cytokine IL-15 [25]. TGF-b supports the differentiation of CD103+ TRMs. However, inflammatory cytokines type I IFN, IL-12, and IL-33 can directly suppress this process [26, 27]. The plasticity of TRMs is an important topic. The plasticity mechanism of TRMs still requires extensive research and exploration. Moreover, there is currently no consensus on whether plasticity is beneficial to the human body or weakens the function of specialized immune cells.
5. TRMs in inflammatory skin diseases
The skin is the largest organ in the body. It contains a large number of T cells, up to 2 x 1010 cells, twice the number of T cells in the blood [28]. Roughly speaking, approximately 50% of skin T cells possess the molecular phenotype characteristics of TRMs, and they have been considered to be related to the recurrence and chronic course of inflammatory diseases [14].
5.1 Psoriasis
Psoriasis is a chronic recurrent skin disease closely related to T cell immune disorders, with plaque-type psoriasis being the most common type. It is characterized by thickened red plaques and silvery scales predominantly occurring on the scalp, trunk, and extensor surfaces. Psoriasis shows substantial negative effects on patient quality of life. The pathophysiology characteristics of psoriasis are abnormal proliferation of keratinocytes and infiltration of immune cells in the dermis and epidermis. It involves the innate and adaptive immune systems, with IL-23–IL-17 axis as the principal [29].
A certain number of T cells are often seen infiltrating the skin lesions, including Th17, Th 22, and Tc17 cells [30, 31]. These cells can secrete various cytokines closely related to the occurrence/development of psoriasis, including IL-17, TNF-α, and IFN-γ. The importance of these cytokines has been demonstrated by the therapeutic effects of biological antibodies that block individual cytokines, including TNF-α, IL-23/IL-12p40, IL-23p19, IL-17A, and IL-17 receptors [32, 33].
As is well known, commonly used immunosuppressive therapy can alleviate psoriasis skin lesions by blocking the aforementioned cytokines, but it cannot further prevent disease recurrence. Moreover, recurrent psoriasis lesions often occur in the areas where the original lesions have subsided, suggesting the possibility of pathological immune memory.
Previous research by the author has shown that the molecular levels of CD69, IL-17A, and VEGFA in the remission area of psoriasis still maintain similar high levels to adjacent recurrent skin lesions, indicating that the remission area of the skin lesion still has a risk of recurrence. Moreover, research showed that the high expression of T cell-related genes (LCK and TRCB1) and inflammatory genes (IL-17, IL-22, and IFNG) still existed in the relief skin lesions after 3 months of relief, indicating that active T cells still reside in it [34]. Further research has confirmed that several months after effective treatment of psoriasis vulgaris with methotrexate, NB-UVB, and anti-IL-12/23 biological antibodies, CD4 + TRMs secreting IL-17 and CD8 + TRMs secreting IL-22 still existed in the epidermis of the subsided skin lesions. These further confirm that TRMs play a crucial role in the recurrence of psoriasis [31].
It is shown that TRMs in psoriasis lesions exhibit a CD8 + CD69+ / CD4 + CD69+ phenotype, or CD8 + CD103+ / CD4 + CD103- phenotype, or another phenotype. These are determined by the local immune microenvironment and disease progression. If CD49a is used as the marker for classification, as mentioned earlier, TRMs in psoriasis are often CD8 + CD103 + CD49a- subgroup that mainly secretes IL-17A [24, 32]. In general, in psoriasis, CD4 + T cells mainly infiltrate the dermis and almost do not express CD103. CD8 + T cells infiltrating the epidermis are positive for CD103, while most cells in the dermis are CD103-. Therefore, most epidermal T cells are CD8 + CD103 + TRMs. Some CD8 + CD103 + TRMs exist in the papillary layer and subpapillary layer. The number of CD8 + CD103 + TRMs in the epidermis is often correlated with epidermal thickness [35], which supports the role of TRMs in the formation of psoriasis lesions.
Whether it is CD4+ or CD8 + T cells, the IL-17A-secreted subgroup in psoriasis lesions can be collectively referred to as TRM17 [36]. Of course, there are also studies that only refer to the CD8 + IL-17 + subgroup as TRM17 [37]. IL-23 is crucial for maintaining autoimmune inflammation in non-lymphocytic tissues. Research has confirmed that the application of anti-IL-23 receptor antibodies in mice after the remission of primary Candida albicans infection led to the loss of skin TRM17 cells. Moreover, clinical treatment with anti-IL-23 antibodies can significantly reduce TRM117 cells in the skin lesions of psoriasis patients [36]. Correspondingly, compared with other targeted biological agents, anti-IL-23 antibodies have the lowest recurrence rate in clinical treatment of psoriasis. These results demonstrate that locally produced IL-23 promotes
5.2 Vitiligo
Vitiligo is a skin disease with acquired depigmentation, and it is currently believed that autoimmunity plays a role in the impaired number/function of melanocytes. According to the distribution of lesions, vitiligo can be divided into three different forms: non-segmental, segmental, and mixed-type vitiligo. Vitiligo is associated with genetic polymorphisms involved in immune response and melanogenesis. Its occurrence also involves environmental factors. The following vitiligo refers to non-segmental type.
The pathophysiology of vitiligo is complex, and more and more evidence suggests that CD8+ TRMs, especially the CD49a + subgroup, are involved in the recurrence of vitiligo [38]. CD8 + CD49a + TRMs in vitiligo have been demonstrated to constitutively express perforin and granzyme B, thus exhibiting a strong cytotoxic phenotype. Even in the skin perilesional vitiligo, CD8 + TRMs highly express CD69, CD103, and CXCR3, and exhibit increased IFN-γ and TNF- α production and moderate cytotoxicity activity [24, 39].
IL-15 can promote the survival of TRMs in vitiligo. Research has shown that IL-15-deficient mice exhibit impaired TRM cell formation. Targeting IL-15 signaling with antibodies against CD122 (IL-15 receptor subunit) can inhibit the production of IFN-γ by TRMs, even deplete TRMs from skin lesions, and reverse the established mouse vitiligo model [40]. These studies emphasize not only the role of TRMs in vitiligo recurrence but also provide new potential targets for the treatment of vitiligo.
5.3 Fixed drug eruption and SJS/TEN
Fixed drug eruption (FDE) is a well-defined, circular, erythematous, or violaceous plaque that recurs as one or a few lesions always in fixed locations (e.g., the genitals, lips, and trunk) upon ingestion of a medication of the same or similar structure.
It occurs in exactly the same location as the first instance, indicating the existence of immune memory. The predominance of the CD8 + memory T cell population within the epidermis has been demonstrated in FDE lesions, and they can produce IFN-γ and TNF-α. These T cells constitutively express CD69 and CD103. In addition, the rate of production of IFN-γ is much faster than their peripheral counterparts [14]. IL-15 is crucial in the pathogenesis of FDE. It is mainly derived from the lesional keratinocytes. Even without antigen stimulation, it can maintain the survival of CD8 + memory T cells in the epidermis for a long period of time (>4 years) [41].
Unlike FDE, Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) are at the extremely severe end of drug eruption spectrum, and may endanger the patient’s life. Skin TRMs have been recognized to play a crucial role in the pathogenesis of SJS and TEN [42, 43]; However, more direct evidence is currently needed.
The SJS/TEN-like skin adverse reactions caused by immune checkpoint inhibitors (ICIs) also involve the role of TRMs. ICIs target immune checkpoint molecules, such as programmed cell death protein 1 (PD-1), PD ligand 1 (PD-L1), and cytotoxic T-lymphocyte-associated protein-4 (CTLA-4). The corresponding antibodies include: pembrolizumab and nivolumab targeting PD-1; atezolizumab, avelumab, and durvalumab targeting PD-L1; ipilimumab against CTLA-4. ICI-driven activation of the immune system can induce various immune-related adverse events (irAEs). Among them, cutaneous irAEs (cirAEs) are the most common and earliest to occur. The cirAEs are characterized by a wide range of phenotypes, including life-threatening SJS/TEN [44].
This mechanism of cirAEs may involve various immune cells, including T cells. The blockade of PD-1 and CTLA-4 enhances the activity of IL-17, IFN-γ, and IL-2-producing T-cells [45, 46]. In addition, research has shown that nivolumab treatment can upregulate granular enzyme B and IFN-γ in lesions of metastatic melanoma patients [47]. The clinical and histopathological characteristics of SJS/TEN induced by ICI are similar to those caused by other classic drugs. It is speculated that PD-L1 is usually not detected in epidermal keratinocytes, but ICI treatment increases the expression of PD-L1, thereby activating cytotoxic CD8 + T cells and inducing apoptosis in keratinocytes with high expression of PD-L1 [46, 48]. It is undeniable that the mechanism of SJS/TEN induced by ICIs is still unclear. Whether the cytotoxic CD8 + T cells involved fully conform to the characteristics of TRMs, that is, whether these cytotoxic CD8 + T cells have a memory function, needs further clarification. Furthermore, innate immunity clearly plays a crucial role in this process, but research in this area is still insufficient. Clarifying these immunological characteristics and mechanisms helps to ensure that immunotherapy for cancer patients can be carried out as much as possible, as this is more important for patients.
5.4 Other inflammatory skin diseases
More and more evidence suggests that TRMs are also involved in the progression of other inflammatory skin diseases, such as alopecia areata [49], atopic dermatitis [50], and cutaneous lupus erythematosus [51, 52]. Due to space limitations, we will not elaborate further here.
6. Conclusion
Skin TRMs are important guardians of the human body barrier. They play an important role in defending against pathogen invasion. However, in uncontrolled pathological conditions, TRMs have become one of the important causes of the recurrence of inflammatory skin diseases due to their characteristics of long-term survival (longevity) and long-term residence. Further clarification of the mechanisms of TRMs in terms of residence, survival, and activation will be of great help in developing corresponding intervention targets to reduce disease recurrence.
Acknowledgments
Part of the research work involved in this chapter was supported by the National Natural Science Foundation of China (No. 82073444, 82273537).
Nomenclature
Aryl hydrogen receptor | |
Cutaneous immune-related adverse events | |
Cytotoxic T-lymphocyte-associated protein-4 | |
Ddendritic cells | |
Fatty acid binding protein | |
Fatty acids oxidation | |
Immune checkpoint inhibitors | |
Immune-related adverse events | |
Programmed cell death protein 1 | |
Programmed cell death protein ligand 1 | |
Sphingosine-1-phosphate | |
Sphingosine 1-phosphate acid receptor type 1 | |
Stevens-Johnson Syndrome | |
Toxic Epidermal Necrolysis | |
Tissue-resident memory T cells |
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