Cells In Pathogenesis Research Articles

Anti-ICOS mAb Targets Pathogenic IL-17A-expressing Cells in Canine Model of Chronic GVHD.

Chronic graft-versus-host disease (GVHD) is a significant cause of morbidity and mortality in transplant patients. We have previously shown that 3 doses of an anti-inducible costimulator (ICOS) mAb transiently ameliorated symptoms and extended survival of dogs affected by chronic GVHD over that of control dogs. The purpose of this study was to specifically correlate changes in T-cell populations in the peripheral blood with anti-ICOS treatment and chronic GVHD progression and regression to reach a better understanding of the mechanism of the disease and prioritize future studies. Peripheral blood cells from canines transplanted with DLA-mismatched bone marrow and peripheral blood mononuclear cells to generate chronic GVHD were analyzed by flow cytometry using a panel of antibodies specific to helper and cytolytic T cells. Chronic GVHD was specifically associated with an increase in CD4+ICOS+ cells, ICOS+ cells expressing IL-17A, and CD8+ cells generating granzyme B. Treatment with anti-ICOS mAb at onset of chronic GVHD symptoms specifically targeted IL-17A+-expressing cells, transiently relieved symptoms, and lengthened survival but was unable to reduce the percentage of CD8+ T-cells expressing granzyme B. These studies suggested a role for both CD4+ and CD8+ T cells in pathogenesis of chronic GVHD in the canine model. We propose that future studies should focus on further extending survival by developing a treatment that would control both CD4+ and CD8+ T cells.

Deviant proteome profile of equine granulocytes associates to latent activation status in organ specific autoimmune disease

Equine recurrent uveitis (ERU) is a spontaneous, remitting-relapsing autoimmune disease driven by the adaptive immune system. Although T cells are described as the main effector cells in pathogenesis, granulocytes have also emerged as possible disease mediators. To explore the role of these innate immune cells, we investigated the whole cell proteome of granulocytes from equine recurrent uveitis cases and healthy controls. Among the 2362 proteins identified by mass spectrometry, we found 96 proteins with significantly changed abundance between groups (p < 0.05, fold change >1.2), representing 4.1% of total granulocyte proteome. Within these differential identifications, calgranulin B, a protein associated with pathogenesis in other autoimmune diseases, showed highest abundance in equine recurrent uveitis (18 fold).For a better interpretation of the results from our hypothesis-generating approach, we added a threshold for biological significance (ratio ERU/controls >2: 36 proteins) to the proteins with increased abundance in equine recurrent uveitis and analyzed their allocation to the subsets within the Immune System superpathway. The 36 differentially abundant proteins predominantly associated to RAF/MAP kinase cascade, MHC-I-mediated antigen presentation and neutrophil degranulation, suggesting a latently activated phenotype of these innate immune cells in disease. Raw data are available via ProteomeXchange with identifier PXD013648. SignificanceOur study provides new insights into the protein repertoire of primary equine granulocytes and identifies protein abundance changes associated to equine recurrent uveitis (ERU), an organ specific, spontaneously occurring autoimmune disease. We show that granulocyte proteins with increased abundance in ERU strongly associate to RAF/MAP kinase signaling, MHC-I antigen presentation and neutrophil degranulation, pointing to a more activated state of these cells in ERU cases. Since cells were obtained in quiescent stage of disease, latent activation of granulocytes underlines the role of these innate immune cells in ERU.These findings are highly relevant for veterinary medicine, further establishing the importance of granulocytes in this T cell-driven autoimmune disease. Moreover, they have translational quality for autoimmune uveitis in man, due to strong similarity in disease occurrence, progression and pathogenesis.

Concealed role of red blood cells in pathogenesis of pulmonary arterial hypertension: Decreased red blood cell nitric oxide generation and effect of Rho-Kinase inhibitor fasudil.

Pulmonary arterial hypertension (PAH) is a devastating disease characterized with alterations in pulmonary vasculature yielding increased pulmonary arterial resistance. Emerging evidences suggest important regulatory roles of red blood cells (RBCs) on nitric oxide (NO) bioavailability, mainly by modulating their endothelial nitric oxide synthase (eNOS) enzyme activity. The aim of this pilot study was to evaluate the alterations in RBC eNOS activity and intracellular NO generation in PAH patients and the modulatory effects of Rho-Kinase (ROCK) inhibitors. RBCs were isolated from patients with PAH and age-matched healthy subjects and were analyzed for their eNOS activity and NO generation capacity under the conditions of the presence or absence of ROCK inhibitor, fasudil. Phosphotidylserine (PS) exposure was also defined. eNOS activity and intracellular NO generation were lower in RBC from PAH patients. ROCK inhibitor increased basal eNOS activity and improved NO generation capacity of RBC of PAH patients to healthy control levels. PS exposure levels were also higher in RBC of PAH patients. This study provides first evidences for decreased RBC eNOS activity due to its ROCK mediated negative regulation in PAH patients. Considering increased ROCK activity contribution to progression of PAH, ROCK inhibition influences NO bioavailability through RBC eNOS, in addition to endothelial eNOS.

Ustekinumab Inhibits T Follicular Helper Cell Differentiation in Patients With Crohn's Disease.

Background & aimsThe pathogenesis of chronic inflammatory bowel diseases (Crohn’s disease [CD] and ulcerative colitis) involves dysregulated TH1 and TH17 cell responses, which can be targeted therapeutically by the monoclonal antibody Ustekinumab directed against the joint p40 subunit of IL-12 and IL-23. These cytokines may also regulate the differentiation of T follicular helper (TFH) cells, which promote B cell function in germinal centers. However, the role of TFH cells in CD pathogenesis and impact of Ustekinumab therapy on TFH cell fate in patients are poorly defined.MethodsLymphocytes were isolated from peripheral blood (n=45) and intestinal biopsies (n=15) of CD patients or healthy controls (n=21) and analyzed by flow cytometry to assess TFH cell phenotypes and functions ex vivo. In addition, TFH cell differentiation was analyzed in the presence of Ustekinumab in vitro.ResultsTFH cell frequencies in the intestine as well as peripheral blood were associated with endoscopic as well as biochemical evidence of CD activity. CD patients with clinical response to Ustekinumab, but not those with response to anti-TNF antibodies, displayed reduced frequencies of circulating TFH cells in a concentration-dependent manner while the TFH phenotype was not affected by Ustekinumab therapy. In keeping with this notion, TFH cell differentiation was inhibited by Ustekinumab in vitro while TFH cell maintenance was not affected. Moreover, Ustekinumab therapy resulted in reduced germinal center activity in CD patients in vivo.ConclusionsThese data implicate TFH cells in the pathogenesis of CD and indicate that Ustekinumab therapy affects TFH cell differentiation, which may influence TFH-mediated immune functions in UST-treated CD patients.

Leishmania donovani metacyclic promastigotes colonize inflammatory monocytes by impairing phagosome function

Abstract Protozoan parasites of the Leishmania genus are the etiological agents of leishmaniasis, a debilitating disease with a wide spectrum of clinical symptoms ranging from self-healing ulcers to life-threatening visceral pathologies. These vacuolar pathogens are transmitted to mammalian hosts as metacyclic promastigotes by the bite of an infected sandfly. Parasites are then internalized by various phagocyte populations such as inflammatory monocytes. The nature of Leishmania-monocyte interactions over the course of infection and the specific role of these cells in pathogenesis are still unclear. Here, we aimed to investigate the impact of Leishmania donovani metacyclic promastigotes on inflammatory monocyte antimicrobial responses. Our results first show that these cells are highly permissive to L. donovani infection, while bacteria are rapidly eliminated. Upon internalization, L. donovani promastigotes inhibit phagosome acidification, as detected by confocal microscopy using the acidotropic probe LysoTracker. Furthermore, these parasites inhibit NOX2 assembly at the parasitophorous vacuole. Indeed, we found that the membrane-bound subunit gp91phox and the cytosolic subunit p47phox are excluded from the PV membrane. As a result, L. donovani metacyclic promastigotes prevent the production of reactive oxygen species within the PV, as detected using NitroBlue Tetrazolium. Permissiveness of inflammatory monocytes to L. donovani may thus be related to the ability of this parasite to impair the microbicidal properties of phagosomes. The virulence factors involved in these processes are currently being investigated.

Novel insights into dendritic cells in the pathogenesis of systemic sclerosis.

SummarySystemic sclerosis (SSc) is a severe autoimmune fibrotic disease characterized by fibrosis, vasculopathy, and immune dysregulation. Dendritic cells (DCs) are the most potent antigen‐presenting cells, specialized in pathogen sensing, with high capacity to shape the immune responses. The most recent technological advances have allowed the discovery of new DC subsets with potential implications in inflammatory conditions. Alterations of DC distribution in circulation and affected tissue as well as impaired DC function have been described in SSc patients, pointing towards a crucial role of these cells in SSc pathogenesis. In particular, recent studies have shown the importance of plasmacytoid DCs either by their high capacity to produce type I interferon or other inflammatory mediators implicated in SSc pathology, such as chemokine C‐X‐C motif ligand 4 (CXCL4). In‐vivo models of SSc have been vital to clarify the implications of DCs in this disease, especially DCs depletion and specific gene knock‐down studies. This review provides these new insights into the contribution of the different DCs subsets in the pathogenesis of SSc, as well as to the novel developments on DCs in in‐vivo models of SSc and the potential use of DCs and their mediators as therapeutic targets.

Research progress in human induced pluripotent stem cells in pathogenesis of cardiomyopathy

心肌病是一组异质性心肌疾病，表现为心律失常、心力衰竭甚至是心源性猝死。人类诱导性多能干细胞是一种具有分化潜能的细胞，为研究心肌病潜在致病机制及药物筛选提供了重要的平台。现对人类诱导性多能干细胞在研究心肌病发病机制中的研究进展进行综述。.

The Epigenetics of Lupus Erythematosus.

Systemic lupus erythematosus (SLE) is a life-threatening autoimmune disease that is characterized by dysregulated dendritic cells, T and B cells, and abundant autoantibodies. The pathogenesis of lupus remains unclear. However, increasing evidence has shown that environment factors, genetic susceptibilities, and epigenetic regulation contribute to abnormalities in the immune system. In the past decades, several risk gene loci have been identified, such as MHC and C1q. However, genetics cannot explain the high discordance of lupus incidence in homozygous twins. Environmental factor-induced epigenetic modifications on immune cells may provide some insight. Epigenetics refers to inheritable changes in a chromosome without altering DNA sequence. The primary mechanisms of epigenetics include DNA methylation, histone modifications, and non-coding RNA regulations. Increasing evidence has shown the importance of dysregulated epigenetic modifications in immune cells in pathogenesis of lupus, and has identified epigenetic changes as potential biomarkers and therapeutic targets. Environmental factors, such as drugs, diet, and pollution, may also be the triggers of epigenetic changes. Therefore, this chapter will summarize the up-to-date progress on epigenetics regulation in lupus, in order to broaden our understanding of lupus and discuss the potential roles of epigenetic regulations for clinical applications.

Analysis of expression of p53, p63 and proliferating cell nuclear antigen proteins in odontogenic keratocyst: An immunohistochemical study.

Background:Odontogenic keratocyst (OKC) is a benign intraosseous lesions (within the jaw bone) of odontogenic origin that account for about 10% of jaw cysts. They are characterized by an aggressive behavior with a relatively high recurrence rate. Early diagnosis and follow-up of the patient with OKC is important because the possibility of such patient there is develop to other features of Nevoid basal cell carcinoma syndrome in future. Considering the roles and effects of p53, p63 and proliferating cell nuclear antigen (PCNA) in cells proliferation, this study was designed.Objectives:To understand the behavior of epithelial cells in pathogenesis and biological aspects of OKC in diagnosis.Materials and Methods:Immunohistochemical (IHC)technique was performed in 21 cases of OKCs.Results:Immunological stained p53 cells were mainly located in the suprabasal layers. p63 and PCNA-positive cells were found throughout the lining epithelium including basal and suprabasal cell layers. The intensity of staining was more in p63 and PCNA than the p53 expression of the cystic epithelial lining.Conclusions:It is possible that the biological behavior of OKCs may be related to the suprabasal proliferative compartment in the cystic epithelium as observed. These proteins may participate in the regulation of epithelial cell differentiation. Taken together, these data may favor tumerigenesis on OKCs.

Cell-to-Cell Spreading of HIV-1 in Myeloid Target Cells Escapes SAMHD1 Restriction.

Dendritic cells (DCs) and macrophages as well as osteoclasts (OCs) are emerging as target cells of HIV-1 involved in virus transmission, dissemination, and establishment of persistent tissue virus reservoirs. While these myeloid cells are poorly infected by cell-free viruses because of the high expression levels of cellular restriction factors such as SAMHD1, we show here that HIV-1 uses a specific and common cell-to-cell fusion mechanism for virus transfer and dissemination from infected T lymphocytes to the target cells of the myeloid lineage, including immature DCs (iDCs), OCs, and macrophages, but not monocytes and mature DCs. The establishment of contacts with infected T cells leads to heterotypic cell fusion for the fast and massive transfer of viral material into OC and iDC targets, which subsequently triggers homotypic fusion with noninfected neighboring OCs and iDCs for virus dissemination. These two cell-to-cell fusion processes are not restricted by SAMHD1 and allow very efficient spreading of virus in myeloid cells, resulting in the formation of highly virus-productive multinucleated giant cells. These results reveal the cellular mechanism for SAMHD1-independent cell-to-cell spreading of HIV-1 in myeloid cell targets through the formation of the infected multinucleated giant cells observed in vivo in lymphoid and nonlymphoid tissues of HIV-1-infected patients.IMPORTANCE We demonstrate that HIV-1 uses a common two-step cell-to-cell fusion mechanism for massive virus transfer from infected T lymphocytes and dissemination to myeloid target cells, including dendritic cells and macrophages as well as osteoclasts. This cell-to-cell infection process bypasses the restriction imposed by the SAMHD1 host cell restriction factor for HIV-1 replication, leading to the formation of highly virus-productive multinucleated giant cells as observed in vivo in lymphoid and nonlymphoid tissues of HIV-1-infected patients. Since myeloid cells are emerging as important target cells of HIV-1, these results contribute to a better understanding of the role of these myeloid cells in pathogenesis, including cell-associated virus sexual transmission, cell-to-cell virus spreading, and establishment of long-lived viral tissue reservoirs.

320.8: Identification of biomarkers for risk, diagnosis, and prognosis of GVHD after bowel transplantation and central role of graft resident memory T cells in pathogenesis

Introduction: Graft-versus-host disease (GVHD) is a relatively common and highly morbid complication after intestinal transplantation. Its pathophysiology remains poorly understood. Resident memory T cells (TRM) are a newly described T cell subset with memory phenotype localizing to peripheral tissue. We hypothesized that the pathophysiology of GVHD might be related to increased donor TRM in the graft that subsequently migrate into host blood and tissue. Methods: Intestinal transplantation from deceased donors was performed using our standard method. Graft and blood lymphocytes from 10 patients with GVHD and 34 without were longitudinally analyzed using flow cytometry. Results: Levels of CD4 and CD8 TRM were approximately 20% higher in the grafts of GVHD vs. stable patients prior to implantation and significantly higher at the time of GVHD (p = 0.02 and 0.04). There was also a mean 60.3% higher level of CD8 TRM in the native bowels of GVHD patients compared to controls and 20–30% higher levels of IFN-γ and TNF-α expression in both the grafts and native bowels of GVHD patients. The percentage of CD4 and CD8 TRM in the blood of GVHD vs. stable patients significantly increased during GVHD (p = 0.005), and expression of HLA-DR, CD57, and PD-1 was significantly higher. There were also significant increases in CD8 effector memory cells (p = 0.0056) and decreases in naïve cells (p = 0.0034). Notably, CD8/PD-1 was also significantly elevated prior to transplantation in patients who later had GVHD (p = 0.025), and a pre-transplant CD8/PD1 level >45% was an absolute predictor of later GVHD. Moreover, we found significantly higher percentages of HLA-DR, CD57, and PD-1 in patients with GVHD who died vs. those who survived, and values that always correlated with mortality were CD8/CD57 > 35%, CD4/HLA-DR > 15%, CD8/HLA-DR > 45%, and CD4/PD1 > 35%. Conclusion: In the largest longitudinal analysis to date, we demonstrate that increased TRM percentage and inflammatory cytokine expression in graft bowel correspond with increased TRM in blood and native bowel as well as increased cytokine expression in native bowel at time of GVHD. Thus GVHD pathogenesis may depend on donor TRM in graft bowel migrating to the blood and native tissue of recipients. Recipients with higher PD-1 expression, indicating T cell exhaustion, might be more vulnerable, providing a possible biomarker for GVHD risk, while increased expression of maturity and activation markers correlate with prognosis.

Role of regulatory T cells in pathogenesis and therapy of autoimmune liver disease

Role of regulatory T cells in pathogenesis and therapy of autoimmune liver disease

Lack of association between serum IL-9 levels and Behçet’s disease

IntroductionConsidering the role of interleukin (IL)-9 and IL-9-producing Th9 cells in pathogenesis of autoimmune diseases, this study aimed to evaluate serum IL-9 levels in patients with Behçet’s disease (BD) compared to healthy subjects and to assess whether there is an association between serum IL-9 levels and disease characteristics in BD. MethodologyIn this cross-sectional study, 32 BD patients according to the International Criteria for BD (ICBD) and 56 age-matched healthy controls were included. In patients, clinical examination was performed and Behcet’s Disease Current Activity Form (BDCAF), Iranian Behcet’s Disease Dynamic Activity Measure (IBDDAM) and Total Inflammatory Activity Index (TIAI) were assessed. Serum IL-9 level was measured using ELISA kit. ResultsThe mean ± SD age of patients and controls was 39.06 ± 9.86 and 38.64 ± 8.40 years, respectively and 41% of patients and 66% of controls were males. The most common clinical symptoms in BD patients were oral aphthous ulcers, ocular involvement, and genital ulcers, respectively. The median (Min–Max) of BDCAF, IBDDAM and TIAI in patients were 2 (0–4), 1.3 (0–7), and 2 (0–22), respectively. There was no significant difference in serum IL-9 levels between BD patients (47.12 ± 7.34 mg/dL) and healthy controls (48.61 ± 7.76 mg/dL) (P > 0.05). There were no significant correlations between serum IL-9 levels with BD clinical characteristics as well as with disease severity (P > 0.05). ConclusionOur study revealed no significant difference in serum IL-9 between BD patients and healthy controls as well as no significant correlation between serum IL-9 with clinical characteristics and disease severity. Further studies are certainly needed, but on a wider cohort of BD patients to identify IL-9 involvement in BD pathogenesis.

Roles of Regulatory T Cells in Pathogenesis of Endometriosis

Numerous studies have shown aberrant immune cell function in endometriosis, including T cells, B cells, natural killer cells, and macrophages (MΦ). These alterations are thought to be induced by various mechanisms that promote the disease. Regulatory T cells (Tregs) may account for a decreased ability of newly recruited leukocytes to initiate effective immune responses against viable endometrial fragments, permitting their survival. Tregs differentiate during the development of endometriosis, which confer immunosuppression or play other roles in disease progression. In this review, we provide an overview of the regulation and roles of Tregs in endometriosis. These data provide further scientific evidence for the altered immune response in endometriosis, which could be a potential target in the treatment of endometriosis. This review could create new diagnostic strategies and effective immune-targeted therapies for this highly prevalent disease. Recent progress in the field indicates that these goals may be achieved in the future.

Microglia are not required for prion-induced retinal photoreceptor degeneration

Degeneration of photoreceptors in the retina is a major cause of blindness in humans. Often retinal degeneration is due to inheritance of mutations in genes important in photoreceptor (PR) function, but can also be induced by other events including retinal trauma, microvascular disease, virus infection or prion infection. The onset of apoptosis and degeneration of PR neurons correlates with invasion of the PR cellular areas by microglia or monocytes, suggesting a causal role for these cells in pathogenesis of PR degenerative disease. To study the role of microglia in prion-induced retinal disease, we fed prion-infected mice a CSF-1 receptor blocking drug, PLX5622, to eliminate microglia in vivo, and the effects on retinal degeneration were analyzed over time. In mice not receiving drug, the main inflammatory cells invading the degenerating PR areas were microglia, not monocytes. Administration of PLX5622 was highly effective at ablating microglia in retina. However, lack of microglia during prion infection did not prevent degeneration of PR cells. Therefore, microglia were not required for the PR damage process during prion infection. Indeed, mice lacking microglia had slightly faster onset of PR damage. Similar results were seen in C57BL/10 mice and transgenic mice expressing GFP or RFP on microglia and monocytes, respectively. These results were supported by experiments using prion-infected Cx3cr1 knockout mice without PLX5622 treatment, where microglial expansion in retina was delayed, but PR degeneration was not. Contrary to predictions, microglia were not a causative factor in retinal damage by prion infection. Instead, newly generated PrPSc accumulated around the inner segment region of the PR cells and appeared to correlate with initiation of the pathogenic process in the absence of microglia.

Differential expression of CD1a and s-100 by dendritic cells in different forms of leprosy–possible role of dendritic cells in pathogenesis

Differential expression of CD1a and s-100 by dendritic cells in different forms of leprosy–possible role of dendritic cells in pathogenesis

Investigation of follicular helper T cells, as a novel player, in preeclampsia.

Preeclampsia (PE) is characterized by hypertension and proteinuria. It occurs in an around 3% to 5% of all pregnancies worldwide. The fetus is kind of semiallograft to the maternal host; immune system components encounter fetal antigens and develop adverse immune responses. Recently, it has been observed that the immune system plays an important role in PE. In the current study, we have tried to investigate the role of follicular helper T (Tfh) cells in the pathogenesis of PE. Blood samples of 49 PE women and 50 healthy controls were collected. Peripheral blood mononuclear cellswere isolated, cells were cultured, and then RNA was extracted. Autoantibody and secretory cytokine levels were analyzed by ELISA. Tfh frequency and transcription levels of the related molecules and cytokine were assessed by flow cytometry and real-time PCR, respectively. The frequency of circulating Tfh cell in PE women was significantly higher compared with the healthy pregnant woman (Tfh cells with CD4+ ICOS + , P = 0.0064 and Tfh cells with CD4 + CXCR5 + , P = 0.029). Moreover, mRNA expression levels of CXCR5, BCL6, IL-21, and IL-6 ( P = 0.0006, P = 0.008, P = 0.0063, and P = 0.027, respectively) were upregulated in PE patients. Furthermore, IL-6 ( P = 0.0014) and IL-21 ( P = 0.0059) levels in both group were assayed and the results showed increased in patient group. We also measured autoantibody levels including antiphospholipid antibodies ( P = 0.0001), anticardiolipin antibodies ( P = 0.0004), anti-TPO ( P = 0.0008), anti-TG ( P = 0.001) in circulation of PE group, which were higher than the control group. This study provided insights into the involvement of Tfh cells in etiology and pathogenesis of PE, probably by developing autoantibodies.

The Role of Lgr5 Stem Cells in Pathogenesis of Ameloblastoma

The Role of Lgr5 Stem Cells in Pathogenesis of Ameloblastoma

Serum BAFF and APRIL levels in Indian patients with Takayasu arteritis.

Despite many studies focused on involvement of T cell in pathogenesis of Takayasu arteritis (TaK), very few have explored the role of B cells. Hence, we sought evidence of B cell involvement in a large cohort of TaK by measuring serum levels of B cell survival factors activation factor (BAFF) and A proliferation inducing ligand (APRIL). Serum BAFF and APRIL levels were measured by ELISA in 50 patients and 48 healthy individuals, and further assessed for correlation with outcome measures, such as Indian Takayasu Clinical Activity Score-ESR (ITAS-ESR) and Takayasu arteritis Damage score (TADS). Forty women and ten men of median age 26 (11-52) and disease duration of 3years (0.1-22) were studied. Type V disease was the most common subset (n = 31), while type I, II, III, and IV was seen in ten, four, three, and two patients respectively. Serum APRIL levels were raised in patients as compared to healthy controls [2087.5pg/ml (1480.0-2279.0) vs. 1288.64pg/ml, (844.2-1632.9) p = 0.01]. Median serum APRIL level was also raised in patients with active disease (n = 24) as compared to inactive disease (n = 26) 2098.79pg/ml, (1930.75-2768.75) vs. 1802.5pg/ml, (1066.75-2098); p = 0.03). Serum BAFF levels were not raised in patients with TaK when compared to healthy Individuals. Neither BAFF, nor APRIL levels correlated with disease activity (ITAS-ESR) or TADS. Elevated APRIL levels in active TaK suggest probable role of B cells in pathogenesis.

T Cell Hierarchy in the Pathogenesis of Psoriasis and Associated Cardiovascular Comorbidities.

The key role of T cells in the pathogenesis of cutaneous psoriasis has been well described in the last decade and the knowledge of the relative role of the different subsets of T cells in psoriasis pathogenesis has considerably evolved. Now, it is clear that IL-17A-producing T cells, including Th17/Tc17, have a central role in the pathogenesis of cutaneous psoriasis and therapies blocking the IL-17A pathway show high clinical efficacy. By contrast, the contribution of IFNγ-producing T cells has progressively become less clear because of the lack of efficacy of anti-IFNγ antibodies in clinical studies. In parallel, the role of CD8+ T cells specific for self-antigens has been revived and increasing evidence now indicates that in psoriatic skin the majority CD8+ T cells are present in the form of epidermal tissue-resident memory T cells. In the last years it also emerged the possibility of a contribution of T cell recirculation in the pathogenesis of psoriasis and its systemic manifestations. The aim of this review is to define a hierarchy for the different subsets of T cells in the T cell-mediated inflammatory cascade in psoriatic skin. This analysis will possibly help to distinguish the subsets that initiate the disease, those involved in the establishment of the self-sustaining amplification loop that leads to the cutaneous clinical manifestations and finally the subsets that act as downstream players in established lesions. Specific T cell subpopulations finally will be considered for their possible role in propagating inflammation at distant sites and for representing a link with systemic inflammation and cardiovascular comorbidities.