The identification of an additional subset of helper T cells (Th17), Th1 and Th22 cells, as well as their distinct sets of cytokines (IL-23, IL-12, and IL-22), has paved the way for the development of more novel and targeted treatments.

AMPs are comprised of 12-50 amino acids, have a positive charge, and have an amphipathic structure. They help protect the host by destroying harmful bacteria, protozoa, fungus, and viruses (38,39). AMPs act as chemotactic agents, angiogenic factors, and cell proliferation regulators, affecting host inflammatory responses (39). In psoriasis, certain AMPs, including S100 proteins, cathelicidins and beta-defensins are overexpressed and secreted by keratinocytes, macrophages and neutrophils in response to injury and cytokine stimulation (40).

The S100 proteins are a group of low-molecular-weight proteins (9-13 kDa) (41). Psoriasis patients have high levels of S100A7 (psoriasin), S100A8 (calgranulin A), S100A9 (calgranulin B), S100A12 (calgranulin C), and S100A15 (calgranulin C) (42). The expression of beta-defensin 2, S100A9, S100A7, and S100A8 was enhanced synergistically by the combination of IL-22, IL-17A, IL-17F, and keratinocytes (43). In psoriasis, S100A7 (psoriasin) has been found to be a strong and selective chemotactic inflammatory protein for T cells and neutrophils (44).

Defensins are cationic microbicidal peptides that are divided into three categories, i.e., α, β and γ (42). The α-defensins are also classified into six subtypes known as human neutrophil peptides (HNPs) 1-6. HNPs 1-3 are present in the scales of psoriatic lesions (45). The β-defensins are divided into four subtypes identified as human β-defensins (hBDs) 1-4. TNF-α and IFN-γ induce hBD-2 and -3, which are abundant in psoriatic scales, while IL1-7A and IL-22 also induce hBD-2 in keratinocytes (39). The exact role of defensins in the pathophysiology of psoriasis is unknown (46).

Cathelicidin LL-37 is the C-terminal peptide fragment that originates from hCAP18(47). Through Toll-like receptor (TLR)9 pDCs recognize self-DNA, and LL-37 is the main component that causes pDC activation in psoriasis (48). In addition, keratinocytes are exposed to LL-37 and self-DNA generate type I IFN, which have been linked to the onset of psoriasis (49). pDCs are stimulated by LL-37 bound to RNA through TLR7 and LL-37-RNA complexes act on myeloid DCs (mDCs) through TLR8 (40,46,49).

TNF, IL-23, and IL-12 are produced by activated mDCs when they move into draining lymph nodes. Slan⁺ monocytes also react to LL-37-RNA activation and release TNF, IL-23, and IL-12(50). IL-23 and IL-12 activate Th17 and Th1 cell subsets from naive T cells, respectively (40). Mabuchi and Hirayama verified in a study that various 9-mer peptides generated from LL-37 have significant binding affinities for HLA-C*06:02 molecules, and they hypothesized a mechanism for the interaction of LL-37 HLA-C*06:02 complexes with T cells via T-cell receptors (51).

ADAMTSL5, a protein produced from melanocytes, has been identified as an autoantigen (52). In association with HLA-C*06:02, intra-epidermal CD8 T lymphocytes identify ADAMTSL5 on melanocytes (52). With IL-17 stimulation, keratinocytes generate ADAMTSL5, and CXCL1, a neutrophil chemoattractant and melanocyte growth factor, inducing ADAMTSL5 expression (52). The number of melanocytes increases in psoriasis, and T cells, including cytotoxic T cells, co-localize with them (53). However, as the number of melanocytes increases and there are no indications of cell death in psoriasis, it is hypothesized that melanocytes are likely targets of the non-cytotoxic CD8⁺ T cell-mediated autoimmune response (54).

The pattern of T-cell infiltration and DC aggregation in the superficial dermis in psoriasis, which is analogous to LL-37(55), is mirrored by the ADAMTSL5 expression pattern. After therapy with an IL-17 or TNF blocker, the expression of ADAMTSL5 and LL-37 with DCs, neutrophils, macrophages, and T cells in psoriasis is markedly reduced (56,57). This decrease suggests that HLA-class II molecules present ADAMTSL5 and LL-37 to autoreactive CD4⁺ T cells, whereas HLA-Cw6*02 molecules present ADAMTSL5 and LL-37 to CD8⁺ T cells, both of which are expressed on the surface of antigen-presenting cells inside dermal lymphoid tissue structures (52,57). In psoriasis patients, a synthetic ADAMTSL5 peptide enhances the frequency of CD8 T cells expressing IL-17A and IFN-7 among peripheral blood mononuclear cells, but this effect is not observed in healthy subjects (52).

pDCs are important cells involved in the early stages of psoriasis. pDCs can be stimulated by viral and bacterial particles by activating Toll-like receptors (TLR)7 and TLR9, resulting in the production of type 1 interferon (IFN-α) (58). IFN-α is a key cytokine involved in the initiation phase of autoimmune responses and antiviral immunity, causing an inflammatory response, associated with psoriasis, through the activation of mDCs (59,60). IFN-α upregulation has been found in early psoriatic lesions (61). Furthermore, in a mouse xenograft model of psoriasis, the formation of psoriatic lesions was found to depend on IFN-α production by pDCs (60).

The mechanism by which pDCs generate a psoriasiform response is partly elucidated by observational experiments with imiquimod (59,62,63), a synthetic imidazoquinoline recognized by TLR7(64). pDCs are induced to produce type I IFN-α (62,63) and interferon regulatory factor 7 (IRF7) (65) when imiquimod is applied to the non-lesional skin of susceptible patients (63). pDCs respond in a similar way when they detect bacterial and viral peptides (59,62,63).

In vivo, the antimicrobial peptide LL-37 is found to be a major activator of pDCs. It has been postulated that the release of LL-37 by activated keratinocytes and the subsequent binding of the molecule to self-DNA in susceptible individuals causes conformational changes in the bound DNA molecule, transforming this otherwise harmless molecule into an aggregated, dense structure recognized by early ribosomal TLR9, resulting in IFN-α production but not pDC maturation. As a result, LL-37-activated pDCs move into the epidermis, where they identify autoantigens produced by keratinocytes, potentially perpetuating the pathogenic process (48,66). According to this theory, dysregulated LL-37 may serve as a link between keratinocytes and pDCs in the pathogenesis of psoriasis (48). Through interactions with HLA-DR and class-I alleles, LL-37 is related to the activation of both CD4⁺ and CD8⁺ LL37-specific psoriatic T cells (66).

In psoriatic skin, the number of mDCs is significantly increased. An inflammatory subset of mDCs [including TNF-α and iNOS-expressing dendritic cells (TIP-DCs), 6-sulfo LacNAc dendritic cells (slanDCs), and epidermal dendritic cells (eDCs)] has been detected in lesional psoriatic skin in response to the release of IFN-α and other proinflammatory cytokines and chemokines (50,67-71).

Once activated, mDCs orchestrate the inflammatory phases of psoriasis. Inflammatory mDCs also co-express cytokines such as TNF-α, iNOS, and IL-12, which are all well-known inflammatory mediators. TNF-α (also released by keratinocytes) activates mDCs and Langerhans cells, and stimulates macrophages to convert into DCs (68).

TNF-α is produced by mDCs, which are powerful APCs that generate a variety of inflammatory cytokines that impact T-cell activity. IL-23, a cytokine that promotes the differentiation of precursor CD4⁺ cells into Th17 cells, and IL-12, a cytokine that promotes the formation of Th1 cells and effector CD8⁺ T cells (50,71,72) are also produced by mDCs. mDCs influence keratinocytes and the skin vasculature by producing IL-20 (a keratinocyte function modifier) and nitric oxide (a vasodilator) (73).

The hypothesis of a cytokine network in psoriasis suggests a major involvement of proinflammatory cytokines, including TNF-α (74). In reflection, the clinical effectiveness of anti-TNF medication in the treatment of psoriasis has confirmed this theory (75). The major cytokines that appear to be involved in this disease, based on gene signature analysis, include type I interferons, IFN-γ, and TNF-α (76).

In early psoriasis lesions, type I interferon pathways are upregulated (61). pDCs produce the majority of IFN-α in psoriatic skin. The finding that systemic therapy with IFN-α can aggravate psoriasis (77,78) provides evidence in favor of IFN-α, playing a significant role in psoriasis. Furthermore, topical therapy with imiquimod, which causes local IFN-α production in the skin, has been shown to promote the development of psoriasis in individuals and a psoriasis-like condition in mice (79,80). The psoriasis-like condition develops in mice lacking a transcription factor that suppresses type I interferon signaling (81).

TNF-α is a proinflammatory cytokine that is common in a variety of inflammatory diseases, including psoriasis (82). TNF-α is produced and responded to by activated dendritic cells, Th17 and Th1 cells, and keratinocytes in psoriatic skin. TNF-α also promotes disease development by interacting with other cytokines.

The evidence of elevated TNF-α levels in the lesional skin of psoriatic individuals (83), marked clinical improvement in psoriasis with pharmacologic inhibitors of TNF-α (infliximab, adalimumab, etanercept, and certolizumab pegol) (75,84-87) and decreased numbers of dendritic and T cells, as well as a reduction in epidermal hyperplasia through removing circulating TNF-α with etanercept (a TNF-α inhibitor) in psoriatic skin (69), suggests that TNF-α plays an essential role in psoriasis. TNF-α is a prominent target for therapeutic inhibition because of its major involvement in both innate and adaptive immune responses.

IL-23 produced by DCs and downstream products of helper T cells, such as IL-17A and IL-22, are also important (88,89).

In psoriasis, key cytokines function via a limited number of signaling and transcriptional pathways. Cytokine-like type I interferons, IFN-γ, IL-23, IL-12, IL-22 function via Janus kinases and signal transducers and activators of transcription (JAK-STATs), while TNF-α operates through the NF-κB pathway (3).

The IL-23p19 subunit (encoded by IL-23A) and the IL-12/IL-23p40 subunit (shared with IL-12 and encoded by IL-12B) form a heterodimer. The subunit binds to the IL-23R receptor, which is linked to Jak2 and Tyk2. When the receptor is activated, a signaling cascade is triggered, which includes the activation of STAT3(90).

Evidence of IL-23 involvement in psoriatics is sustained by the fact that IL-23 levels are higher in psoriasis lesions compared to unaffected skin, and it is found in dermal DCs and keratinocytes; IL-23 levels decrease with effective psoriasis treatment (91-93). In support of this, injection of IL-23 into normal mouse skin causes clinical and histological alterations that are similar to psoriasis (92,94,95). This process is dependent on the downstream generation of IL-22 and IL-17A. Furthermore, results from a mouse model revealed that, blocking IL-23 inhibited the development of psoriasis in human xenografted skin from patients with psoriasis (96).

IL-12 is produced by activated mDCs, similar to IL-23, and it stimulates Th1 cell development. Increased Th1 cells and IFN-γ (a product of Th1 cells) in psoriatic skin provide indirect evidence for an IL-12-related role in psoriasis (97,98). The inability of a study to detect the overexpression of the IL-12 p35 subunit in psoriatic skin (88) casts doubt on the extent to which IL-12 contributes to psoriasis. Preclinical mouse studies also suggest that IL-12 has a regulatory or protective role in the IL-23/Th17 immunologic pathway (99). It is probable that ustekinumab, a type of biological therapy for psoriasis that targets both IL-12 and IL-23 (96,100), may function primarily through the drug's effects on the IL-23 pathway.

As a result, a complex and partly redundant set of psoriasis-related cytokines converge on well-known intracellular checkpoints that are common to many chronic inflammatory diseases. T cells, in particular, are the key protagonists in the disease's development among all the diverse immunological cellular elements. In fact, the IL-23/Th17/IL-17 axis now appears to have a determining effect on the beginning of psoriasis inflammation (101).

CD4 helper T cells are detected in dermal inflammatory infiltrates of psoriatic skin (102). An injection of CD4 (but not CD8) T cells from psoriasis patients into graft sites on SCID mice transplanted with human skin-generated psoriatic alterations in the grafted skin is evidence for a role for these cells (103). Furthermore, patients with psoriasis who were treated with monoclonal antibodies against the CD4 molecule on T cells improved clinically (104).

Psoriasis has been linked to the Th17 subset of CD4 T cells, as well as Th1 and Th22 cells to a lesser extent. Th1 cells were thought to have a dominant role in early research, but Th17 cells are now thought to play a more important role. The impact of these cells, as well as other adaptive immune system components, on psoriasis are discussed below.

The identification of Th17 cells has resulted in new target-specific therapy methods and critical insights into the pathogenesis of psoriasis. Th17 cells originate in psoriatic skin as a result of the polarizing effects of the inflammatory DC production of IL-1, IL-6, TGF-β, and IL-23(105). Th17 cells, that have been activated by IL-23, generate IL-17A and IL-22, cytokines that promote keratinocyte activation and development (94,106,107).

The following study results highlight the role of these cells in psoriasis: IL-17A is abundantly produced by Th17 cells that are observed in lesional skin and at higher levels in the circulation in psoriasis patients (97,108,109). Th17 cells secrete a number of proinflammatory cytokines, including IL-17A, IL-17F, IL-21, IL-22, IL-6, and TNF-α (110), which have all been related to psoriasis. In fact, IL-17 is a critical cytokine in the initiation and maintenance of inflammation, as it stimulates endothelial cells and macrophages to produce pro-inflammatory cytokines (111).

Selective targeting of IL-17A (the principal effector cytokine produced by Th17 cells) with secukinumab and ixekizumab, as well as bimekizumab's dual blocking of IL-17A and IL-17F, improves psoriasis (112-114). Brodalumab, which blocks the IL-17RA portion of the IL-17A receptor, has had similar success in treating psoriatic skin (115).

IL-23, which is produced by macrophages and DCs, is important for upregulating IL-17 production by promoting Th17 survival and proliferation (116). It also appears to be necessary for keratinocytes to participate in inflammation, causing acanthosis and mixed inflammatory cell infiltration of the dermis (95). IL-23 is also responsible for increasing TNF production in macrophages.

A viable treatment method for psoriasis is by inhibiting IL-23 or the IL-23 receptor, therefore affecting Th17 cells (117-119). Ustekinumab, a highly successful psoriasis treatment, is a monoclonal antibody that binds to p40, a subunit of both IL-23 and IL-12 that causes Th17 cells to die. Guselkumab, tildrakizumab, risankizumab, and mirikizumab are other selective IL-23 blockers with high efficacy in clinical practice and clinical trials. Psoriasis is also being studied with agents that disrupt the JAK/STAT signaling pathways (key intracellular processes in Th17 cytokine generation) (120-122).

Th1 cell production is enabled by IL-12, a cytokine generated by activated mDCs. It is unclear how IL-12-mediated actions contribute to psoriasis (88). IFN-γ, IL-2, and TNF-α are among the proinflammatory cytokines produced by Th1 cells (123). In non-lesional psoriatic skin, IFN-γ, the prototypic cytokine produced by these cells, can cause psoriasis-like alterations (124). Of note is that infliximab, an effective anti-TNF medication for psoriasis, can also arrest Th1 cells from producing IFN-γ (125).

Cytotoxic CD8 T cells that are mostly present in the epidermis of psoriatic skin, produce cytolitic enzymes and play a smaller role in psoriasis than CD4⁺ T cells via the production of inflammatory cytokines such as IL-17A (126-128). The predominance of Th1/IFN-γ and pro-inflammatory cytokines, occurs in the chronic phase (129,130), as opposed to the IL-23/Th17/IL-17 axis that has a major role in the onset of psoriasis inflammation (131). Indeed, the disease is marked by an increase in cytokines from the Th1 pathway (IL-2, IFN-γ, IL-12, and TNF-α) (132,133). Furthermore, IFN-γ, TNF-α, IL-18, and IL-12 levels in the peripheral blood are proportionally associated with the severity of psoriasis (36). IFN-γ, in particular, suppresses keratinocyte death, resulting in hyperproliferation in psoriatic skin (134-136). Notably, clonal restriction of resident memory epidermal T cells seems limited to the CD8⁺ compartment (137). As these types of MHC class I-restricted antigens are normally presented in CD8 T cells, rather than CD4 T cells, this finding suggests a relationship between viral or self-antigens in the epidermis and triggering of psoriasis (138).

T cells are present in healthy skin. Following exposure to an antigen, naive T cells evolve into effector T cells that can act as immunological defense mechanisms. Subsequent to the immune response most of these cells die; however, some survive and differentiate into memory T cells. Although central memory T cells (TCM) traffic through lymphoid tissues, effector memory cells (TEM) circulate through peripheral tissues. TRM T cells are a newly identified subset of memory T cells that remain in tissues over a long period of time without circulating in the bloodstream, thereby serving as a first line of adaptive cellular defense (139). However, growing evidence suggests that the abnormal activation of these cells may be involved in the pathogenesis of autoimmune and inflammatory disorders, rendering these cells a potentially novel therapeutic target (140). Approximately 20 billion TRMs are present in healthy adult skin (141).

TRMs differ from traditional TCMs and TEMs in terms of transcription, phenotype, and function. They act as alarm sensors or cytotoxic killers in the T-cell zones of secondary lymphoid organs, lymph, and non-lymphoid tissues including the skin (137,140,142,143).

The aim of TRMs is to defend non-lymphatic tissues against viral and bacterial infections. These cells have also been demonstrated to protect against HSV infection, vaccinia pox, lymphocytic choriomeningitis virus (LCMV), influenza, listeriosis, malaria, and various types of cancer (144).

Immunization involves, among other things, training TRMs how to react rapidly to an infection (145). TRMs are prevalent in numerous tissues and provide a more effective in situ response to infectious pathogens compared to TEMs. Granzyme B, which is useful in the prevention of prevent pathogens from spreading at the infection site, is released. TRMs are also capable of stimulating the innate and adaptive responses of the immune system (146-148). TRMs are cells that connect the adaptive and innate immune systems. They also promote protective immune responses for previously encountered tissue as numerous viruses have tissue tropism. However, mounting evidence suggests their involvement in the pathogenesis of autoimmune diseases including psoriasis, vitiligo, autoimmune hepatitis and rheumatoid arthritis (140), in addition to their protective functions.

Depending on the tissue of residency and the nature of the pathogen, TRMs have variable expression of different markers. As a result, they may exist as distinct subsets with phenotypic heterogeneity. CD8⁺ cells that express CD103, CD69, and CD49a are optimally characterized TRMs (149).

CD103 (α_E integrin chain) binds to E-cadherin, thereby fostering retention within epithelial tissues (150). Only CD8⁺ TRMs express the CD103 marker (integrin E subunit), not CD4⁺ TRM cells. Its expression is the most prominent on epidermal CD4⁺ and CD8⁺ TRMs because it allows them to bind to E-cadherin, which is widely expressed by epithelial cells (143,151,152).

CD69 is a T-cell activation marker and is involved in distinguishing T cells in tissues from those in circulation and it is responsible for the colonization of TRMs in tissues, preventing them from recirculating. CD69 expression mediates early T-cell retention in the skin by blocking sphingosine 1-phosphate receptor 1 (S1PR1)-mediated egress from tissues (153). CD69 expression is preceded, followed by CD103. Specifically, the former marker, i.e., greatly impacts the early attachment of TRMs in tissue, whereas the latter (CD103) is involved in their persistence subsequent to reaching the skin. The absence of these surface molecules induces a reduction in the TRM cell population, but not a total elimination (143).

CD49a (the α-subunit of the α₁β₁ integrin receptor, also known as very late antigen VLA-1) is another TRM cell marker. CD49a determines a subset of CD8⁺ TRMs that are localized in the epidermis. In the skin, CD8⁺CD49a⁺ TRMs, which are abundant in vitiligo, produce perforin, granzyme B, and IFN-γ, the last of which is a key cytokine in fighting viral infections. In addition, CD8⁺CD49a⁺ TRMs acquire high cytotoxic capacity upon IL-15 stimulation (154,155). These cells, on the other hand, do not express high quantities of these cytolytic molecules in the absence of external stimulation, and thus differ from circulating CD8⁺ T cells (156). Psoriasis is caused by CD8⁺CD49^- TRMs that generate IL-17 and concentrate in the skin (154,155). TRMs also expresses the surface proteins that suppresses T-cell activity, such as program cell death protein-1 (PD-1) and T-cell immunoglobulin mucin receptor 3 (TIM3). The expression of these proteins occurs in inflamed tissues. In such situations, TRMs exert an anti-inflammatory effect, indicating the ambiguous character of these cells (157,158).

In psoriasis, Th1 and Th17 phenotype CD4⁺ T cells are considered the most pathogenic T-cell subpopulations. A clearer understanding has been gained of the role of LL-37 (an antimicrobial peptide formed from keratinocytes) and ADAMTSL5 (a protein produced by melanocytes) in the etiology of psoriasis. The proteins listed above are known as autoantigens. LL-37 is also recognized as an autoantigen by CD4 T cells, and it correlates with the Psoriasis Area Severity Index (PASI) (52,66). In psoriatic epidermis, CD8⁺ T lymphocytes with TRM phenotype are numerous, but CD4⁺ TRMs preferentially occupy the dermis. The differences in colonization are caused by the presence of CD69, which inhibits the sphingosine-1-phosphate receptor (S1P1), which normally allows lymphatic entrance. A considerable proportion of skin TRMs also expresses CD103, the α_Eβ₇ integrin chain that interacts with E-cadherin expressed by keratinocytic cells. TGF-β through TGF-RII is the signal essential for their survival (145). Hair follicles, through IL-15 and IL-7 production, are also important in their recruitment (159). In addition to cytokines, lipids found in the skin are necessary for the maintenance of TRMs.

TRMs have been identified in recurrent psoriasis sites in unaltered and cured skin, indicating their involvement in the local memory of the disease (160). Memory T-cell recirculation between the skin and circulation is a recently identified immunological mechanism that plays a key role in the onset of the psoriasiform response (161-163). The pathogenicity of TRMs is determined by their ability to generate the pro-inflammatory cytokines IL-17 and IL-22, which are important in this process (158,162).

The experiment of Boyman et al (164) was the first to show the significance of resident cutaneous T lymphocytes in psoriasis. Authors of that study used immunodeficient mice (AGR129 mice, which lack type I and II interferon receptors, as well as the recombination activating gene 2) to implant unchanged human psoriatic skin. Within 8 weeks, the reproduction of resident human T lymphocytes and the establishment of psoriatic lesions were detected. They were mostly found in the epidermis and dermal-epidermal junction, and they had the CD8⁺ phenotype with TNF-α susceptibility (164).

CD4⁺ T cells, which produce pro-inflammatory cytokines such as IL-17A, IL-22, and IFN-γ, are thought to be the predominant pathogenic T-cell subpopulation, but CD8⁺ memory T cells, which are found in healthy skin, have a similar pro-inflammatory cytokine profile. These cells can identify peptide antigens presented on MHC class I molecules, including HLA-Cw6, and are abundant in the psoriatic epidermis (162). On the murine AGR model of psoriasis, blocking 1-integrin arrested T cells from entering the epidermis, which reduces disease eruptions (126). Di Meglio et al (162) demonstrated that an increase in epidermal CD8⁺ cells causes keratinocyte hyperproliferation as well as papillomatosis (an increase in CD8⁺ cells that corresponds to the intensity of Ki67 staining in keratinocytes) (162). Psoriasis-related cytokines are produced by CD8⁺ T lymphocytes isolated from psoriasis patients. These cytokines remain in the skin after treatment, as TRMs and LL-37-specific CD8⁺ T cells that express integrin α₁β₁ (162).

The optimal treatment time required to totally silence TRMs and ensure that lesions do not recur at the same site remains to be determined (165). As a result, psoriatic lesions reappear more frequently in previously affected skin areas, and pathogenic TRMs exposed to IL-17A and IL-22 accumulate in resolved lesions (137,166). Sérézal et al (167) investigated tissue responses after T-cell stimulation in healthy and psoriatic lesions. An increase in the number of epidermal IL-17 and IL-22 (producing skin-resident T CCR6⁺ cells) may be a genetically predisposed response to microbial stimulation in never-lesional skin in psoriasis patients. As a result, IFN-γ production increases, and keratinocytes that produce INF-α are stimulated, causing psoriatic inflammation.

Psoriasis plaques, on the other hand, revealed IL-17-induced response patterns, indicating a relapse. The proportional amount of induced IFN-γ, IL-10e, and IL-17A was associated with the time it took for patients to relapse after stopping treatment (167).

Biopsies from psoriatic lesions were examined in a study by Kurihara et al (151). The number of CD8⁺CD103⁺ TRMs in the epidermis was shown to be linked with epidermal thickness (P=0.016), suggesting an important role in the development of psoriatic lesions (151). The majority of TRMs were CD8⁺CD69⁺ T cells that expressed skin colonization antigens, with a modest number of CD4⁺CD103⁺ TRMs. IFN-γ, IL-17A, and IL-22 were generated by some of the CD8⁺CD103⁺ T cells. Furthermore, CD8⁺CD103⁺ TRMs produced more IL-17A than CD8⁺CD103^- and effector cells CD8⁺CD103⁺ or CD4⁺CD103⁺. The number of CD8⁺CD103⁺IL-17A⁺ TRMs was higher in individuals who received biological or systemic therapy (151). TRMs, on the other hand, expressed less CD103 in the dermis of psoriatic plaques, as demonstrated by Cheuk et al (137). Epidermal TRMs expressing CCR6 collaborate with CCL20-expressing keratinocytes in the early stages of psoriatic inflammation, in the skin where lesions are absent (166,168).

Vo et al (168) investigated the phenotypic characteristics of TRMs in non-lesional, lesional, and healthy skin. When compared to the skin of healthy subjects, an immunofluorescence study revealed that CD103⁺CD8⁺ TRMs were prevalent in both non-lesional and lesional epidermis. Furthermore, individuals with a longer disease duration produced more IL-17A (168).

Diani et al (169) investigated the phenotype of circulating T lymphocytes in psoriasis patients using gene expression analysis in psoriatic skin. The percentage of CCR6⁺CD4⁺ TEMs and TEMs in the blood was found to be positively connected with the severity of skin lesions and inflammation (CRP, C-reactive protein), while the percentage of CXCR3⁺CD4⁺ TEMs was found to be negatively correlated. Furthermore, the severity of psoriasis was negatively correlated with CLA⁺CD4⁺ TCMs expressing CCR6⁺ or CCR4⁺CXCR3⁺. CLA expression has been linked to the recruitment of CD4⁺ T cells into the skin, particularly when expressed on TCMs, especially CD4⁺ TCMs with the CCR4⁺ and CCR6⁺ phenotype (52,169). In a previous study, Bosè et al (170) demonstrated that the inhibition of the CCR7/CCL19 axis was required for psoriasis remission produced by TNF inhibitors (161). In psoriasis, circulating CCR4⁺CD4⁺ T cells have a substantial correlation with the PASI, while CCR5⁺CD4⁺ T cells have a strong negative correlation (170). Systemic inflammation (CRP) and the severity of skin lesions are both strongly correlated with a subpopulation of T effector CCR4⁺CD8⁺CD103⁺ cells (171,172). The fraction of IL-17 secreting CD4⁺ T lymphocytes, and likely γδ T-lymphocytes, was also found to play a role in the creation of a self-sustaining inflammatory loop (169).

TRM suppression is necessary for complete remission of the disease. TRMs, however, have a long lifespan and are resistant to both harmful agents and apoptosis. This explains the reason for frequent psoriasis relapses in the same area. TRMs are capable of generating IL-17A even after the clinical lesions have resolved, and effective therapy merely reduces their activity (161,165). CD8⁺ TRMs also accumulate in untreated psoriasis localizations, which is probably related to duration of the disease (140,171). The explanation of memory cell lifespan is a fascinating field of study. One of the reasons is its apoptosis resistance. CD8⁺ (α_Eβ₇) is a heterodimeric marker compound, comprised of CD103 and beta7 subunits, that plays a vital function in the stability of CD8⁺ TRMs by elevating the expression of the anti-apoptotic Bcl-2 molecule (143,151). TRMs, on the other hand, can produce granzyme B (serine protease), which can cause cell death (158). Furthermore, IL-15 is thought to play a role in TRM cell survival (173).

Of note is that the effector T cells generate adenosine triphosphate (ATP) using glycolysis energy, which is less efficient but faster. Endogenously produced fatty acids, glucose catabolism, and oxidative phosphorylation are used by TCMs on the other hand, to support their long-term survival and function (174,175). TCMs use extracellular glucose from the blood to generate fatty acids in the endoplasmic reticulum, using lysosomal acid lipase, which is required for the breakdown of cholesteryl esters and triglycerides in LDL molecules to cholesterol and free fatty acids (FFA). They can be long-lived and react rapidly to antigen owing to such mechanisms (174). Cui et al also revealed that IL-7, a cytokine important for TCM differentiation and survival, increased glycerol transport and triacylglycerol synthesis by upregulating the gene expression of the glycerol channel aquaporin 9, thereby providing substrates for mitochondria via fatty acid oxidation (FAO) (174,176).

However, the metabolic characteristics of TRMs are currently unknown due to a lack of accurate data. CD8⁺ TRMs, on the other hand, are known to establish a transcriptional pathway that includes the overexpression of FABP4 (adipocyte-FABP), FABP5 (epidermal-FABP), CD36 (lipid scavenger receptor), and lipoprotein lipase (cleaves triglycerides to yield FFA and diacylglycerol). In naive T cells, TCMs, or effector memory cells, such activity of genes responsible for the action of these molecules is not found (174).

Pan and Kupper (174) found that mouse CD8⁺ TRMs produced by cutaneous viral infection have a different expression level of genes encoding proteins that mediate intracellular lipid uptake and transport, such as fatty acid-binding protein-FABP4 (adipocyte-FABP) and FABP5 (epidermal-FABP). These are substances that aid in the acquisition and metabolism of exogenous FFAs (174). CD8⁺ TRMs upregulated the gene expression of FABP4/FABP5 in a peroxisome proliferator-activated receptor (PPAR)-γ-dependent manner (174,177). T-specific deficit of these molecules has been found to impair CD8⁺ TRM uptake of exogenous FFA, reducing their long-term survival in vivo, but has no impact on TCM survival in lymph nodes. Furthermore, CD8⁺ TRM skin cells missing FABP4/FABP5 were less effective in protecting mice against cutaneous viral infection (177). This remains to be determined in psoriasis patients as compared to healthy subjects.

In the presence of exogenous FFA, CD8⁺ TRMs revealed increased oxidative metabolism of mitochondria in normal and psoriatic skin in vitro. These findings suggest that FABP4 and FABP5 are important for CD8⁺ TRM maintenance, lifespan, and function, and that CD8⁺ TRMs rely on exogenous FFA and their oxidative metabolism to survive in tissue. FABP4 and FABP5 deficiency has been demonstrated to have no effect on CD8⁺ T-cell proliferation or skin recruitment, but they are required for their long-term survival in the skin (177). Blocking PPAR-γ functions may pave the way for the development of psoriatic lesion therapeutic strategies.

Psoriatic inflammation is exacerbated by oxidative stress. The redox status of CD4⁺ TRMs and its connection with IL-17 response were studied by Esmaeili et al (178). The increased intracellular ROS production in CD⁺ memory T cells in patients with psoriasis reduced the catalase gene expression relative to healthy cells, but there were no differences in the intracellular glutathione levels or plasma total antioxidant capacity. The above diseases, however, seemed to have no impact on the IL-17 response in memory T cells (178).

Finally, regulatory T-cell (Treg) dysfunction, which is primarily involved in maintaining tolerance and avoiding autoimmune diseases, is a key factor in the pathogenesis of psoriasis (179). These Tregs had a decreased function in counterbalancing pathogenic T cells during psoriasis. Notably, Foxp3⁺ Tregs from psoriasis patients can more quickly develop into pathogenic Th17 cells than other Foxp3⁺ Tregs. IL-17A⁺/Foxp3⁺/CD4⁺ triple-positive cells can be found in the skin lesions on a regular basis and can be utilized to determine the severity of psoriasis. Understanding Treg features in psoriasis can therefore aid in the development of immunotherapies to treat disease.