Treg Differentiation Research Articles

Endogenous retroviruses act as a tonic signal for Treg induction and oral tolerance development

Abstract Endogenous retrovirus (ERVs) result from accumulated germline infections by ancient exogenous retroviruses and constitute a sizable proportion of the mammalian genome. Recent findings support the idea that these elements control tissue immune threshold of activation and inflammation. Within this context, our lab has recently described that, in the skin, the beneficial immunity to the microbiota depends on endogenous retrovirus expression. How the crosstalk between ERVs and the microbiota controls tissue immunity at other barrier sites and how dysregulation of this dialogue impairs tolerance responses remain unknown. Our results reveal that antiretroviral (anti-RT) treatment (blocking the conversion of ERV into cDNA) impairs gut regulatory T cell homeostasis and differentiation and compromises the induction of oral tolerance to food antigens. Consistently, our data demonstrate that antiretroviral treatment impairs type I IFN signaling in mucosal dendritic cells involved in the induction of regulatory T cells. Further, our results show that epithelial ERV expression is highly conserved across tissues and seems to be only partially affected by the microbiota in the small intestine. Altogether, our results propose that ERV control immunoregulation within the gastrointestinal tract by acting as a tonic signal required for Treg induction and differentiation thereby promoting oral tolerance and preventing allergic responses. This work was supported in part by intramural funds of NIAID, NIH. C.A.R is supported by Damon Runyon Fellowship program (DRG-2496-23).

Stem-like CD4 T differentiation controls CD8 T cell immunity or tolerance in cancer

Abstract In this work we wanted to understand how CD4 T cell differentiation shapes the CD8 T cell response in cancer. We identified a population of tumor specific CD4 T cells that maintain an activated, undifferentiated phenotype throughout the cancer response. These CD4 T cells were the dominant population within tumor draining lymph nodes (TDLNs), characterized by high expression of TCF1 and little to no expression of other lineage defining transcription factors. Tumor specific TCF1+ CD4s exhibited functional stem-like properties, as they self-renewed and differentiated almost exclusively into Tregs in tumor bearing mice. These cells, however, were not limited to Treg differentiation, as sorted TCF1+ CD4s from a 5-week tumor response expanded and gave rise to TH1 and TFH effectors in response to LCMV Armstrong infection. Interestingly, we also found a similar population of activated PD1+ TCF1+ CD4s with stem-like capabilities infiltrating various human tumors, indicating this phenotype of CD4s is comparable in human cancer and mouse models. Importantly, the choice of lineage differentiation of TCF1+ CD4s regulated the quality of the CD8 T cell anti-tumor response. When Tregs were selectively depleted, TCF1+ CD4s differentiated into TH1s, which enhanced tumor specific CD8 T cell effector differentiation in both tumor and TDLNs, resulting in reduced tumor burden. Using a bone marrow chimeric CRISPR-Cas9 approach, we found that IFNg from TH1s was intrinsically required for CD8 stem to effector differentiation within TDLNs, promoting an improved anti-tumor response. Overall, this work shows that CD4 differentiation dictates tolerance or immunity in cancer by regulating the phenotype and magnitude of the effector CD8 T cell response.

Murine CD4+ T cells exhibit sexually dimorphic responses to estrogen signaling

Abstract Many autoimmune diseases exhibit sexual dimorphism. 17β-estradiol (estrogen, “E2”), a steroid sex hormone primarily known for its reproductive roles, has also been shown to modulate CD4+ T cells. E2 signals through two nuclear receptors, ERα and ERβ, which regulate gene transcription through direct DNA binding and other mechanisms. We previously showed that in the SAMP/YitFC model of Crohn’s-like ileitis, loss of ERβ enhanced inflammation selectively in female mice. We also found that loss of ERβ resulted in decreased expression of Foxp3 in CD4+ T cells, suggesting that ERβ is required for differentiation of Foxp3+ Tregs. These prior findings suggest a pro-inflammatory role for ERα and anti-inflammatory role for ERβ, potentially in a sex-specific manner. In the current study, we investigated mechanisms of E2 signaling in CD4+ T cells isolated from males vs. females. Using standard in vitro assays, we found that the proliferation of TGFβ-induced regulatory T cells (Tregs) was enhanced in female cells co-treated with E2 compared to male cells, suggesting that E2 enhances Treg differentiation more strongly in females. Interestingly, using the CD45RB T cell transfer model of colitis, we found that recipients of female donor cells exhibited more severe disease compared to recipients of male cells, suggesting that female-derived CD45RB highT cells are more colitogenic than male cells. Future studies will determine the effect of E2 signaling on both effector and regulatory CD4+ T cell populations, identifying the contributions of ERα vs. ERβ-specific signaling in these T cell subsets and the functional impact of these signaling pathways in males versus females. Supported by grants from NIH (R01DK128143, R03DK123579, T32AI089474)

Immunomodulatory functions of the gut protist Pentatrichomonas hominis in health and disease

Abstract Protists have been identified as part of the mammalian gut microbiome and are known to impact gut immunity and complex intestinal diseases such as inflammatory bowel disease (IBD). In humans, studies mainly describe host interactions with disease-causing species, while little is known about how commensal protists impact the immune system. Protists from the Parabasalid family, including Pentatrichomonas hominis (P. hominis), have been identified in about 30% of healthy individuals; however, the role of these non-pathogenic commensal Parabasalids remains unstudied. Our data shows that P. hominis promotes Treg differentiation in vitro. Interestingly, this ability was found to be contact-independent, as culture supernatant was sufficient to induce Tregs. Moreover, by doing de-novo genome and transcriptome assembly and high-resolution mass spectrometry we have identified immunomodulatory candidate pathways and metabolites that might be mediating this effect. Re-establishment of tolerance is a major therapeutic strategy for treating intestinal diseases. Hence, we were interested in studying P. hominis impact on the gut immune landscape. To that aim, we successfully and stably colonized mice with P. hominis in gnotobiotic housing conditions and under antibiotic regimen and we are testing P. hominis role under steady state and IBD mouse models. Altogether, our research will address a present gap in knowledge, potentiating the study of protists in the microbiome and their association with intestinal disorders.

HLA-DO promotes Treg differentiation by altering antigen presentation

Abstract HLA-DO in human (H2-O in mice) (DO) is a highly conserved non-classical MHC class II accessory molecule. Unlike the main Class II peptide editor HLA-DM, expression of DO is restricted to the thymic medulla, B cells and certain dendritic cell subsets. DO forms a stable complex with HLA-DM and requires DM for trafficking to MIIC. Using biochemical experiments, our lab has previously discovered that DO has differential effects on editing peptides of different sequences. DO enhances binding of DM-resistant peptides, and reduces the binding of DM-sensitive peptides to the HLA-DR1 molecules. Changes in the quantities of either DM-resistant of DM-sensitive peptides could therefore lead to alterations in both thymic negative selection, and peripheral activation of CD4 T cells. Using single-cell RNA-sequencing (scRNA-seq) of peripheral CD4 T cells from unimmunized DO knock-out (KO) mice we found an increased frequency of “activated” CD4 T cells, in support of our biochemical model. This increased frequency corresponds with a decrease in “naïve” CD4 T cells in both scRNA-seq and FACs analysis. Interestingly, scRNA-seq analysis confirmed our previous findings of elevated regulatory T cells (Treg) levels in DO-KO mice. Genetic analysis showed that unimmunized DO-KO Tregs also have a more activated phenotype. These findings suggests that absence of DO generates a more stimulatory in vivo cellular environment for CD4 T cells, likely due to altered antigen presentation. Research supported by grants from NIH (R01 AI130210, R01 AI121174 and R37 AI060040)

DNA demethylation fine-tunes IL-2 production during thymic development and promotes Regulatory T cell differentiation

Abstract Regulatory T (T reg) cells developing in the thymus are essential to maintain tolerance and prevent fatal autoimmunity in mice and humans. Expression of the T reg lineage-defining transcription factor FoxP3, is critically dependent upon T cell receptor (TCR) and interleukin-2 (IL-2) signaling. Here, we report that ten-eleven translocation (Tet) enzymes, which are DNA demethylases, are required early during double positive (DP) thymic T cell differentiation and prior to the upregulation of FoxP3 in CD4 single-positive (SP) thymocytes, to promote Treg differentiation. We show that Tet enzymes selectively control the development of CD25 −FoxP3 loCD4SPTreg cell precursors and are critical for optimal TCR-dependent IL-2 production, which drive chromatin remodeling at the FoxP3 locus as well as other Treg-effector gene loci in an autocrine/paracrine manner. Together, our results demonstrate a novel role for DNA demethylation in regulating the TCR response and promoting Treg cell differentiation. These findings highlight a novel epigenetic pathway to promote the generation of endogenous Treg cells for mitigation of autoimmune responses.

Targeting glutamine metabolism mitigates Foxp3-deficiency mediated disease

Abstract Regulatory T (Treg) cells play a key role in enforcing peripheral immunological tolerance to self-antigens. Foxp3 has been widely described as a master regulator for Treg differentiation and maintenance of their suppressive functions. Upon Foxp3 loss of function mutations, Foxp3-deficient Tregs (ΔTreg) develop in the thymus, however, these cells present impaired suppressive capacity and an effector T cell (Teff)-like phenotype. Among the Teff-like characteristics is the shift in their metabolism towards glycolysis and enhanced mitochondrial respiration. Metabolomic analysis revealed an increase in glutamine consumption. Here, we used 6-diazo-5-oxo-norleucine (DON), a broad inhibitor of glutamine-utilizing enzymes to treat Foxp3 deficient mice (Foxp3 ΔeGFPiCre), and observed a significant decrease in Teff cell activation, and IFNγ production from both ΔTreg and Teff cells together with a significant increase in survival. This effect was enhanced when we combined DON treatment with a ΔTreg specific Rictor depletion (Foxp3 ΔeGFPiCreRictor Δ/Δ). Given that glutamine is a key amino acid for T cell activation, we evaluated if this was a pan-T cell effect by inducing Treg depletion in Foxp3 DTRmice with concomitant DON treatment. Surprisingly, in the absence of Tregs, DON was not able to prevent autoimmune disease. These results suggest that DON mitigates Foxp3-deficiency mediated disease in a ΔTreg dependent manner, by improving their suppressive capacities. We are currently performing metabolomic studies to better understand the role of glutamine usage in ΔTreg, more specifically if glutamine is directed to glutaminolysis, nucleotide or glutathione synthesis and how this contributes to Treg cell loss of function. NIH grant 1R01AI153174

Inhibition of DYRK1B suppresses inflammation in allergic contact dermatitis model and Th1/Th17 immune response

Allergic contact dermatitis (ACD) is a type IV hypersensitivity mainly mediated by Th1/Th17 immune response. Topical corticosteroid is currently the first-line treatment for allergic contact dermatitis (ACD) and systemic administration of immunosuppressive drugs are used in patients with severe disseminated cases. However, increased risk of adverse effects has limited their use. Thus, the development of a novel immunosuppressant for ACD with low toxicity is a challenging issue. In this study, we began our study by using a murine contact hypersensitivity (CHS) model of ACD to examine the immunosuppressive effects of DYRK1B inhibition. We found that mice treated with a selective DYRK1B inhibitor show reduced ear inflammation. In addition, a significant reduction of Th1 and Th17 cells in the regional lymph node upon DYRK1B inhibition was observed by FACS analysis. Studies in vitro further revealed that DYRK1B inhibitor does not only suppressed Th1 and Th17 differentiation, but also promotes regulatory T cells (Treg) differentiation. Mechanistically, FOXO1 signaling was enhanced due to the suppression of FOXO1Ser329 phosphorylation in the presence of DYRK1B inhibitor. Therefore, these findings suggest that DYRK1B regulates CD4 T cell differentiation through FOXO1 phosphorylation and DYRK1B inhibitor has a potential as a novel agent for treatment of ACD.

Extracorporeal Photopheresis Suppresses Transplant Fibrosis by Inducing Decorin Expression in Alveolar Macrophages.

Extracorporeal Photopheresis Suppresses Transplant Fibrosis by Inducing Decorin Expression in Alveolar Macrophages.

105 A peptide encoded by pri-miRNA-31 represses autoimmunity by promoting Treg differentiation

105 A peptide encoded by pri-miRNA-31 represses autoimmunity by promoting Treg differentiation

Hedgehog Signaling Regulates Treg to Th17 Conversion Through Metabolic Rewiring in Breast Cancer.

The tumor immune microenvironment dynamically evolves to support tumor growth and progression. Immunosuppressive regulatory T cells (Treg) promote tumor growth and metastatic seeding in patients with breast cancer. Deregulation of plasticity between Treg and Th17 cells creates an immune regulatory framework that enables tumor progression. Here, we discovered a functional role for Hedgehog (Hh) signaling in promoting Treg differentiation and immunosuppressive activity, and when Hh activity was inhibited, Tregs adopted a Th17-like phenotype complemented by an enhanced inflammatory profile. Mechanistically, Hh signaling promoted O-GlcNAc modifications of critical Treg and Th17 transcription factors, Foxp3 and STAT3, respectively, that orchestrated this transition. Blocking Hh reprogramed Tregs metabolically, dampened their immunosuppressive activity, and supported their transdifferentiation into inflammatory Th17 cells that enhanced the recruitment of cytotoxic CD8+ T cells into tumors. Our results demonstrate a previously unknown role for Hh signaling in the regulation of Treg differentiation and activity and the switch between Tregs and Th17 cells in the tumor microenvironment.

Fatty acid desaturation by stearoyl-CoA desaturase-1 controls regulatory T cell differentiation and autoimmunity

The imbalance between pathogenic and protective T cell subsets is a cardinal feature of autoimmune disorders such as multiple sclerosis (MS). Emerging evidence indicates that endogenous and dietary-induced changes in fatty acid metabolism have a major impact on both T cell fate and autoimmunity. To date, however, the molecular mechanisms that underlie the impact of fatty acid metabolism on T cell physiology and autoimmunity remain poorly understood. Here, we report that stearoyl-CoA desaturase-1 (SCD1), an enzyme essential for the desaturation of fatty acids and highly regulated by dietary factors, acts as an endogenous brake on regulatory T-cell (Treg) differentiation and augments autoimmunity in an animal model of MS in a T cell-dependent manner. Guided by RNA sequencing and lipidomics analysis, we found that the absence of Scd1 in T cells promotes the hydrolysis of triglycerides and phosphatidylcholine through adipose triglyceride lipase (ATGL). ATGL-dependent release of docosahexaenoic acid enhanced Treg differentiation by activating the nuclear receptor peroxisome proliferator-activated receptor gamma. Our findings identify fatty acid desaturation by SCD1 as an essential determinant of Treg differentiation and autoimmunity, with potentially broad implications for the development of novel therapeutic strategies and dietary interventions for autoimmune disorders such as MS.

Nanoplastics Shape Adaptive Anticancer Immunity in the Colon in Mice.

The impact of nanoplastics (NPs) on human health is still not well understood, and more research is needed to better understand the risks associated with these particles. In this study, we found that oral administration of polyethylene (PE) NPs in a mice model significantly disrupted the intestinal microenvironment, which shapes adaptive immune response and favors the established in situ colorectal tumor growth. Using single-cell RNA sequencing technology, we show that NPs triggered colon IL-1β-producing macrophages by inducing lysosome damage, leading to colonic Treg and Th17 differentiation associated with T cell exhaustion, which creates a colon environment that favors the tumor initiation and progress. A similar effect is also observed in polystyrene NPs. Our result provides insight into the potential link between NPs ingestion and colon tumorigenesis, and the urgency of addressing plastic pollution worldwide.

Tumor-Derived PD-L1+ Exosomes with Natural Inflammation Tropism for Psoriasis-Targeted Treatment.

Psoriasis is a chronic inflammatory disease whose etiology is directly related to the dysregulation of cutaneous immune homeostasis. However, how to finely modulate the skin immune microenvironment to restore homeostasis remains an important challenge. Inspired by the natural attribute of tumor exosomes in the immune escape, the tumor-derived exosomes as an active targeting nanoplatform for the effective treatment of inflammatory skin disorder were first reported. As keratinocytes and immune cells express high PD-1 during the onset of psoriasiform skin inflammation, the PD-L1-positive exosomes derived from melanoma cells carrying pristimerin with extremely anti-inflammatory potential were yielded to treat psoriasis. The PD-L1+ exosomes carrying pristimerin were characterized, and the cellular uptake was performed to evaluate the PD-1 target capability. The anti-inflammatory action of PD-L1+ exosomes carrying pristimerin was observed in both in vitro and in vivo models of psoriasis. Our exosomes substantially increased pristimerin uptake with CD4+ T cells and keratinocytes, significantly inhibited the proliferation of Th17 cells, and promoted Treg differentiation in a psoriasis-like model. Obviously, PD-L1+ exosomes carrying pristimerin significantly and safely reversed imiquimod (IMQ)-induced psoriasis in mice, indicated by reducing epidermal thickness, decreasing plaque formation, and suppressed excessive inflammatory response, due to its dual targeting of both CD4+ T cells and keratinocytes gathering around the lesion. The inflammatory cell infiltration and pro-inflammatory cytokine production in psoriasis were suppressed by our engineered exosomes. Besides, PD-L1+ exosomes carrying pristimerin treatment alleviated ferroptosis-related changes in psoriatic skin, thereby dampening excessive inflammation and, in turn, decreasing the abnormal proliferation of keratinocytes in psoriatic lesions. This study demonstrates that our engineered exosomes can not only act as a treat-to-target strategy for psoriasis treatment but also provide insight in clinical application of inflammatory disorders.

LKB1 isoform expression modulates T cell plasticity downstream of PKCθ and IL-6

Following activation, CD4 T cells undergo metabolic and transcriptional changes as they respond to external cues and differentiate into T helper (Th) cells. T cells exhibit plasticity between Th phenotypes in highly inflammatory environments, such as colitis, in which high levels of IL-6 promote plasticity between regulatory T (Treg) cells and Th17 cells. Protein Kinase C theta (PKCθ) is a T cell-specific serine/threonine kinase that promotes Th17 differentiation while negatively regulating Treg differentiation. Liver kinase B1 (LKB1), also a serine/threonine kinase and encoded by Stk11, is necessary for Treg survival and function. Stk11 can be alternatively spliced to produce a short variant (Stk11S) by transcribing a cryptic exon. However, the contribution of Stk11 splice variants to Th cell differentiation has not been previously explored. Here we show that in Th17 cells, the heterogeneous ribonucleoprotein, hnRNPLL, mediates Stk11 splicing into its short splice variant, and that Stk11S expression is diminished when Hnrnpll is depleted using siRNA knock-down approaches. We further show that PKCθ regulates hnRNPLL and, thus, Stk11S expression in Th17 cells. We provide additional evidence that exposing induced (i)Tregs to IL-6 culminates in Stk11 splicing downstream of PKCθAltogether our data reveal a yet undescribed outside-in signaling pathway initiated by IL-6, that acts through PKCθ and hnRNPLL to regulate Stk11 splice variants and facilitate Th17 cell differentiation. Furthermore, we show for the first time, that this pathway can also be initiated in developing iTregs exposed to IL-6, providing mechanistic insight into iTreg phenotypic stability and iTreg to Th17 cell plasticity.

M6A methyltransferase METTL3 programs CD4+ T-cell activation and effector T-cell differentiation in systemic lupus erythematosus

BackgroundSystemic lupus erythematosus (SLE) is an autoimmune disorder in which excessive CD4+ T-cell activation and imbalanced effector T-cell differentiation play critical roles. Recent studies have implied a potential association between posttranscriptional N6-methyladenosine (m6A) modification and CD4+ T-cell-mediated humoral immunity. However, how this biological process contributes to lupus is not well understood. In this work, we investigated the role of the m6A methyltransferase like 3 (METTL3) in CD4+ T-cell activation, differentiation, and SLE pathogenesis both in vitro and in vivo.MethodsThe expression of METTL3 was knocked down and METTL3 enzyme activity was inhibited using siRNA and catalytic inhibitor, respectively. In vivo evaluation of METTL3 inhibition on CD4+ T-cell activation, effector T-cell differentiation, and SLE pathogenesis was achieved using a sheep red blood cell (SRBC)-immunized mouse model and a chronic graft versus host disease (cGVHD) mouse model. RNA-seq was performed to identify pathways and gene signatures targeted by METTL3. m6A RNA-immunoprecipitation qPCR was applied to confirm the m6A modification of METTL3 targets.ResultsMETTL3 was defective in the CD4+ T cells of SLE patients. METTL3 expression varied following CD4+ T-cell activation and effector T-cell differentiation in vitro. Pharmacological inhibition of METTL3 promoted the activation of CD4+ T cells and influenced the differentiation of effector T cells, predominantly Treg cells, in vivo. Moreover, METTL3 inhibition increased antibody production and aggravated the lupus-like phenotype in cGVHD mice. Further investigation revealed that catalytic inhibition of METTL3 reduced Foxp3 expression by enhancing Foxp3 mRNA decay in a m6A-dependent manner, hence suppressing Treg cell differentiation.ConclusionIn summary, our findings demonstrated that METTL3 was required for stabilizing Foxp3 mRNA via m6A modification to maintain the Treg differentiation program. METTL3 inhibition contributed to the pathogenesis of SLE by participating in the activation of CD4+ T cells and imbalance of effector T-cell differentiation, which could serve as a potential target for therapeutic intervention in SLE.

Treg-targeted efficient-inducible platform for collagen-induced arthritis treatment.

Regulatory T cells (Tregs) display great promise in rheumatoid arthritis (RA) therapy. However, their low number and differentiation rate limit their further application in the clinics. In the present study, we first optimized a combination of IL-2, TGF-β and cyclin dependent kinase inhibitor AS2863619 (IL-2/TGF-β/AS), which could induce Tregs with high efficiency in vitro. After the induced Tregs (iTregs) were confirmed to suppress lymphocyte proliferation and pro-inflammatory T help cells (Th1 and Th17) activation, a chitosan-stabilized nanoparticle drug delivery system (NDDS) was developed according to the optimized formula of IL-2/TGF-β/AS. In vivo study, the NDDS was injected into the knees of mice with collagen-induced arthritis (CIA). As a result, the NDDS remarkably reduced the pathological score of the CIA, alleviated the inflammatory cell infiltration and synovial hyperplasia, and minimized cartilage tissue damage in the knee joint of the CIA mice. Mechanically, the NDDS administration promoted Treg differentiation and decreased Th17 production, consequently reversing the ratio of Treg/Th17, and reducing the secretion of TNF-α in the sera, which facilitated to relieve the severity and progression of arthritis. In sum, NDDS capable of efficiently inducing Tregs were constructed successfully and provided a potential platform for treating RA by restoring the equilibrium of Treg/Th17 destroyed in RA.

Treg cells require Izumo1R to regulate γδT cell-driven inflammation in the skin.

Izumo1R is a pseudo-folate receptor with an essential role in mediating tight oocyte/spermatozoa contacts during fertilization. Intriguingly, it is also expressed in CD4+ T lymphocytes, in particular Treg cells under the control of Foxp3. To understand Izumo1R function in Treg cells, we analyzed mice with Treg-specific Izumo1r deficiency (Iz1rTrKO). Treg differentiation and homeostasis were largely normal, with no overt autoimmunity and only marginal increases in PD1+ and CD44hi Treg phenotypes. pTreg differentiation was also unaffected. Iz1rTrKO mice proved uniquely susceptible to imiquimod-induced, γδT cell-dependent, skin disease, contrasting with normal responses to several inflammatory or tumor challenges, including other models of skin inflammation. Analysis of Iz1rTrKO skin revealed a subclinical inflammation that presaged IMQ-induced changes, with an imbalance of Rorγ+ γδTcells. Immunostaining of normal mouse skin revealed the expression of Izumo1, the ligand for Izumo1R, electively in dermal γδTcells. We propose that Izumo1R on Tregs enables tight contacts with γδTcells, thereby controlling a particular path of skin inflammation.

Assessment of the Potential Role of Selected Single Nucleotide Polymorphisms (SNPs) of Genes Related to the Functioning of Regulatory T Cells in the Pathogenesis of Psoriasis

Recent studies have indicated a key role of the impaired suppressive capacity of regulatory T cells (Tregs) in psoriasis (PsO) pathogenesis. However, the genetic background of Treg dysfunctions remains unknown. The aim of this study was to evaluate the association of PsO development with selected single nucleotide polymorphisms (SNPs) of genes in which protein products play a significant role in the regulation of differentiation and function of Tregs. There were three study groups in our research and each consisted of different unrelated patients and controls: 192 PsO patients and 5605 healthy volunteers in the microarray genotyping group, 150 PsO patients and 173 controls in the ARMS-PCR method group, and 6 PsO patients and 6 healthy volunteers in the expression analysis group. The DNA microarrays analysis (283 SNPs of 57 genes) and ARMS-PCR method (8 SNPs in 7 genes) were used to determine the frequency of occurrence of SNPs in selected genes. The mRNA expression of selected genes was determined in skin samples. There were statistically significant differences in the allele frequencies of four SNPs in three genes (TNF, IL12RB2, and IL12B) between early-onset PsO patients and controls. The lowest p-value was observed for rs3093662 (TNF), and the G allele carriers had a 2.73 times higher risk of developing early-onset PsO. Moreover, the study revealed significant differences in the frequency of SNPs and their influence on PsO development between early- and late-onset PsO. Based on the ARMS-PCR method, the association between some polymorphisms of four genes (IL4, IL10, TGFB1, and STAT3) and the risk of developing PsO was noticed. Psoriatic lesions were characterized with a lower mRNA expression of FOXP3, CTLA4, and IL2, and a higher expression of TNF and IL1A in comparison with unaffected skin. In conclusion, the genetic background associated with properly functioning Tregs seems to play a significant role in PsO pathogenesis and could have diagnostic value.

Expansion and characterization of regulatory T cell populations from Korean kidney transplant recipients.

The development of immunosuppressants has enabled remarkable progress in kidney transplantation (KT). However, current immunosuppressants cannot induce immune tolerance, and their nonspecific immunosuppressive effects result in many adverse effects. Regulatory T cells (Tregs) play crucial roles in controlling all specific immune responses. This study evaluated the distribution of Tregs and their effects on kidney allograft function in Korean KT recipients. We enrolled 113 KT recipients with stable graft function. The differentiation and expansion of Tregs were examined by flow cytometry to compare the Tregs subpopulations. Among the 113 patients, 73 (64.6%) were males, and the mean follow-up period from KT to Tregs collection was 147.5 + 111.3 months. Patients receiving lower doses of cyclosporine had higher proportions of Tregs than those with higher doses of cyclosporine (36.3 + 21.6 vs 17.0 + 12.7, P = .010, respectively). Patients taking cyclosporine tended to have higher Tregs numbers than those taking tacrolimus (94.7 + 158.1 vs 49.3 + 69.4, P = .095, respectively). However, no significant association was observed between Tregs and allograft dysfunction in the cox proportional hazard model. Tregs counts may be associated with the type and dose of immunosuppressants. However, no significant relationship was found between Tregs and kidney allograft function in stable KT recipients.