Th17 Lineage Research Articles

Unique T cell signatures associated with reduced Chlamydia trachomatis reinfection in a highly exposed cohort.

Chlamydia trachomatis (CT) is the most common bacterial sexually transmitted infection (STI) in the United States, despite effective antibiotics. Information regarding natural immunity to CT will inform vaccine design. The objectives of this study were to determine immune cell populations and functional features associated with reduced risk of CT reinfection or endometrial CT infection. PBMCs were collected from a cohort of CT-exposed women who were tested for CT and other STIs at the cervix and endometrium (to determine ascension) and were repeatedly tested over the course of a year (to determine reinfection). Mass cytometry identified major immune populations and T cell subsets. Women with CT had increased CD4+ effector memory T cells (TEM) compared to uninfected women. Specifically, Th2, Th17, and Th17 DN CD4+ TEM were increased. Th17 and Th17 DN CD4+ central memory T cells (TCM) were increased in women who did not experience follow-up CT infection, suggesting that these cells may be important for protection. These data indicate that peripheral T cells display distinct features that correlate with natural immunity to CT and suggest that the highly plastic Th17 lineage plays a role in protection against reinfection.

Dysregulation of T cell response in the pathogenesis of inflammatory bowel disease.

Inflammatory bowel disease (IBD), comprised of Crohn's disease (CD) and ulcerative colitis (UC), are gut inflammatory diseases that were earlier prevalent in the Western Hemisphere but now are on the rise in the East, with India standing second highest in the incidence rate in the world. Inflammation in IBD is a cause of dysregulated immune response, wherein helper T (Th) cell subsets and their cytokines play a major role in the pathogenesis of IBD. In addition, gut microbiota, environmental factors such as dietary factors and host genetics influence the outcome and severity of IBD. Dysregulation between effector and regulatory T cells drives gut inflammation, as effector T cells like Th1, Th17 and Th9 subsets Th cell lineages were found to be increased in IBD patients. In this review, we attempted to discuss the role of different Th cell subsets together with other T cells like CD8+ T cells, NKT and γδT cells in the outcome of gut inflammation in IBD. We also highlighted the potential therapeutic candidates for IBD.

Inherent metabolic preferences differentially regulate the sensitivity of Th1 and Th2 cells to ribosome-inhibiting antibiotics.

Mitochondrial translation is essential to maintain mitochondrial function and energy production. Mutations in genes associated with mitochondrial translation cause several developmental disorders, and immune dysfunction is observed in many such patients. Besides genetic mutations, several antibiotics targeting bacterial ribosomes are well-established to inhibit mitochondrial translation. However, the effect of such antibiotics on different immune cells is not fully understood. Here, we addressed the differential effect of mitochondrial translation inhibition on different subsets of helper T cells (Th) of mice and humans. Inhibition of mitochondrial translation reduced the levels of mitochondrially encoded electron transport chain subunits without affecting their nuclear-encoded counterparts. As a result, mitochondrial oxygen consumption reduced dramatically, but mitochondrial mass was unaffected. Most importantly, we show that inhibition of mitochondrial translation induced apoptosis, specifically in Th2 cells. This increase in apoptosis was associated with higher expression of Bim and Puma, two activators of the intrinsic pathway of apoptosis. We propose that this difference in the sensitivity of Th1 and Th2 cells to mitochondrial translation inhibition reflects the intrinsic metabolic demands of these subtypes. Though Th1 and Th2 cells exhibit similar levels of oxidative phosphorylation, Th1 cells exhibit higher levels of aerobic glycolysis than Th2 cells. Moreover, Th1 cells are more sensitive to the inhibition of glycolysis, while higher concentrations of glycolysis inhibitor 2-deoxyglucose are required to induce cell death in the Th2 lineage. These observations reveal that selection of metabolic pathways for substrate utilization during differentiation of Th1 and Th2 lineages is a fundamental process conserved across species.

Plasticity and lineage commitment of individual TH1 cells are determined by stable T-bet expression quantities.

T helper 1 (TH1) cell identity is defined by the expression of the lineage-specifying transcription factor T-bet. Here, we examine the influence of T-bet expression heterogeneity on subset plasticity by leveraging cell sorting of distinct in vivo-differentiated TH1 cells based on their quantitative expression of T-bet and interferon-γ. Heterogeneous T-bet expression states were regulated by virus-induced type I interferons and were stably maintained even after secondary viral infection. Exposed to alternative differentiation signals, the sorted subpopulations exhibited graded levels of plasticity, particularly toward the TH2 lineage: T-bet quantities were inversely correlated with the ability to express the TH2 lineage-specifying transcription factor GATA-3 and TH2 cytokines. Reprogramed TH1 cells acquired graded mixed TH1 + TH2 phenotypes with a hybrid epigenetic landscape. Continuous presence of T-bet in differentiated TH1 cells was essential to ensure TH1 cell stability. Thus, innate cytokine signals regulate TH1 cell plasticity via an individual cell-intrinsic rheostat to enable T cell subset adaptation to subsequent challenges.

Unique T cell signatures are associated with reduced Chlamydia trachomatis reinfection in a highly exposed cohort.

Abstract Chlamydia trachomatis (CT) is the most common bacterial sexually transmitted infection (STI) in the U.S. despite effective antibiotics. Understanding natural immunity to CT is crucial to inform vaccine design. This study aimed to identify immune cell populations and functional features associated with reduced risk of CT reinfection. PBMCs were collected from 82 CT-exposed women tested for CT and other STIs upon enrollment, and repeatedly over 1 year of follow-up. Immune responses were profiled by mass cytometry. Women with CT at enrollment exhibited higher frequencies of CD4+ effector memory T cells (TEM) than uninfected women. Specifically, Th2, Th17, and Th17 DN CD4 TEM were increased. However, functional features indicated diminished expression of T cell activation and differentiation markers, underscoring weaknesses of natural immunity that could be addressed by vaccine design. Comparing responses in women who remained follow-up negative (FU-) to those who were reinfected (FU+), higher frequencies of Th1, Th17, and Th17 DN CD4 T cells were observed in FU- women. Conversely, Th2 CD4 T cells were increased in FU+ women. Furthermore, markers of T cell differentiation, memory, and cytotoxicity were increased in FU- women. These data indicate that peripheral T cells exhibit distinct features associated with natural immunity to CT. Notably, the highly plastic Th17 lineage appears to contribute to protection. Addressing these immune nuances could promote efficacy of CT vaccines.

Targeting T-bet expressing B cells for therapeutic interventions in autoimmunity.

Apart from serving as a Th1 lineage commitment regulator, transcription factor T-bet is also expressed in other immune cell types and thus orchestrates their functions. In case of B cells, more specifically, T-bet is responsible for their isotype switching to specific IgG sub-classes (IgG2a/c in mice and IgG1/3 in humans). In various autoimmune disorders, such as systemic lupus erythematosus and/or rheumatoid arthritis, subsets of T-bet expressing B cells, known as age-associated B cells (CD19+CD11c+CD21-T-bet+) and/or double-negative B cells (CD19+IgD-CD27-T-bet+), display an expansion and seem to drive disease pathogenesis. According to data, mostly derived from mice models of autoimmunity, the targeting of these specific B-cell populations is capable of ameliorating the general health status of the autoimmune subjects. Here, in this review article, we present a variety of therapeutic approaches for both mice and humans, suffering from an autoimmune disease, and we discuss the effects of each approach on T-bet+ B cells. In general, we highlight the importance of specifically targeting T-bet+ B cells for therapeutic interventions in autoimmunity.

Bhlhe40 Promotes CD4+ T Helper 1 Cell and Suppresses T Follicular Helper Cell Differentiation during Viral Infection.

In response to acute infection, naive CD4+ T cells primarily differentiate into T helper 1 (Th1) or T follicular helper (Tfh) cells that play critical roles in orchestrating cellular or humoral arms of immunity, respectively. However, despite the well established role of T-bet and BCL-6 in driving Th1 and Tfh cell lineage commitment, respectively, whether additional transcriptional circuits also underlie the fate bifurcation of Th1 and Tfh cell subsets is not fully understood. In this article, we study how the transcriptional regulator Bhlhe40 dictates the Th1/Tfh differentiation axis in mice. CD4+ T cell-specific deletion of Bhlhe40 abrogates Th1 but augments Tfh differentiation. We also assessed an increase in germinal center B cells and Ab production, suggesting that deletion of Bhlhe40 in CD4+ T cells not only alters Tfh differentiation but also their capacity to provide help to B cells. To identify molecular mechanisms by which Bhlhe40 regulates Th1 versus Tfh lineage choice, we first performed epigenetic profiling in the virus specific Th1 and Tfh cells following LCMV infection, which revealed distinct promoter and enhancer activities between the two helper cell lineages. Furthermore, we identified that Bhlhe40 directly binds to cis-regulatory elements of Th1-related genes such as Tbx21 and Cxcr6 to activate their expression while simultaneously binding to regions of Tfh-related genes such as Bcl6 and Cxcr5 to repress their expression. Collectively, our data suggest that Bhlhe40 functions as a transcription activator to promote Th1 cell differentiation and a transcription repressor to suppress Tfh cell differentiation.

NF-κB subunits RelA and c-Rel selectively control CD4+ T cell function in multiple sclerosis and cancer.

The outcome of cancer and autoimmunity is often dictated by the effector functions of CD4+ conventional T cells (Tconv). Although activation of the NF-κB signaling pathway has long been implicated in Tconv biology, the cell-autonomous roles of the separate NF-κB transcription-factor subunits are unknown. Here, we dissected the contributions of the canonical NF-κB subunits RelA and c-Rel to Tconv function. RelA, rather than c-Rel, regulated Tconv activation and cytokine production at steady-state and was required for polarization toward the TH17 lineage in vitro. Accordingly, RelA-deficient mice were fully protected against neuroinflammation in a model of multiple sclerosis due to defective transition to a pathogenic TH17 gene-expression program. Conversely, Tconv-restricted ablation of c-Rel impaired their function in the microenvironment of transplanted tumors, resulting in enhanced cancer burden. Moreover, Tconv required c-Rel for the response to PD-1-blockade therapy. Our data reveal distinct roles for canonical NF-κB subunits in different disease contexts, paving the way for subunit-targeted immunotherapies.

Zfp281 and Zfp148 control CD4 + T cell thymic development and T H 2 functions

How CD4 + lineage gene expression is initiated in differentiating thymocytes remains poorly understood. Here, we show that the paralog transcription factors Zfp281 and Zfp148 control both this process and cytokine expression by T helper cell type 2 (T H 2) effector cells. Genetic, single-cell, and spatial transcriptomic analyses showed that these factors promote the intrathymic CD4 + T cell differentiation of class II major histocompatibility complex (MHC II)–restricted thymocytes, including expression of the CD4 + lineage–committing factor Thpok. In peripheral T cells, Zfp281 and Zfp148 promoted chromatin opening at and expression of T H 2 cytokine genes but not of the T H 2 lineage–determining transcription factor Gata3. We found that Zfp281 interacts with Gata3 and is recruited to Gata3 genomic binding sites at loci encoding Thpok and T H 2 cytokines. Thus, Zfp148 and Zfp281 collaborate with Gata3 to promote CD4 + T cell development and T H 2 cell responses.

Cutting Edge: Bach2 Integrates Cytokine Signals to Arbitrate Differentiation Decisions between T Follicular Helper and Th17 Lineages.

CXCR5 is a hallmark of T follicular helper (Tfh) cells. The mechanism of CXCR5 induction, however, is still incompletely understood. In this study, we report that in mice with the absence of transcription factor Bach2, the Th17-inducing cytokines IL-6 and TGF-β together induced CXCR5 expression invitro. Mechanistically, IL-6/STAT3 drove Cxcr5 promoter activity via the upstream site 1 regulatory element, whereas TGF-β enhanced permissive histone modifications, and the STAT3 binding to the site 1 regulatory element was higher in the absence of Bach2. Subsequently, despite previous studies showing enhanced Th17 cell differentiation in the absence of Bach2 invitro, we found that invivo, the Bach2 deficiency led to an enhanced Tfh cell response at the expense of the Th17 cell response. These findings suggest that Bach2 helps integrate cytokine signals to arbitrate differentiation decisions between Tfh and Th17 lineages.

Tet2 deletion in CD4+ T cells disrupts Th1 lineage commitment in memory cells and enhances T follicular helper cell recall responses to viral rechallenge

Following viral clearance, antigen-specific CD4+ T cells contract and form a pool of distinct Th1 and Tfh memory cells that possess unique epigenetic programs, allowing them to rapidly recall their specific effector functions upon rechallenge. DNA methylation programing mediated by the methylcytosine dioxygenase Tet2 contributes to balancing Th1 and Tfh cell differentiation during acute viral infection; however, the role of Tet2 in CD4+ T cell memory formation and recall is unclear. Using adoptive transfer models of antigen-specific wild type and Tet2 knockout CD4+ T cells, we find that Tet2 is required for full commitment of CD4+ T cells to the Th1 lineage and that in the absence of Tet2, memory cells preferentially recall a Tfh like phenotype with enhanced expansion upon secondary challenge. These findings demonstrate an important role for Tet2 in enforcing lineage commitment and programing proliferation potential, and highlight the potential of targeting epigenetic programing to enhance adaptive immune responses.

PI3Kδ shapes Th2 lineage restriction through coordination of IL-2 signaling, Foxo1 inactivation and epigenetic remodeling

Abstract Activated PI3K-delta syndrome (APDS) is a primary immunodeficiency caused by heterozygous activating mutations in PI3Kδ, resulting in recurrent infections as well as allergic diseases. Given that APDS patients show an inability to clear respiratory pathogens (Th1) and development of allergic diseases (Th2), we hypothesized that hyperactivated PI3Kδ (Pik3cd E1020K) may alter CD4 T cell differentiation. Using in vitro polarization of murine naïve CD4 T cells, we observed increased production of IFNγ from Pik3cd E1020Kmice under Th1 inducing conditions and marked increases in IL-4 and IL-13 production under Th2 conditions. However, Pik3cd E1020KTh2 cells also expressed high levels of Tbet and aberrantly produced IFNγ. Strikingly, this dysregulation was also observed in vivo; Pik3cd E1020KCD4 cells show pronounced alterations following house dust mite induced airway inflammation, with impaired Th2 and inappropriate polarization to Th1 responses as visualized by scRNAseq. We linked this unstable Th1 and Th2 differentiation in Pik3cd E1020KCD4 T cells in vitro to hyper-responsiveness to IL-2, associated with increased phosphorylation and inactivation of transcription factor Foxo1. CRISPR-mediated targeting of Foxo1 in naïve WT CD4 cells recapitulated the Pik3cd E1020Kphenotype. Transcriptomic analysis of Pik3cd E1020KCD4 T cells revealed differential expression of genes involved in histone methylation. Accordingly, Pik3cd E1020KCD4 exhibit altered chromatin modifications, including H3K27 and H3K4 trimethylation. Together these data suggest that balanced regulation of PI3Kδ plays a critical role in enforcing Th1 and Th2 lineage identity. This research was supported by the Intramural Research Program of NIAID, NIH

Vδ1+ and Vδ2+ gamma delta T cell subsets exert distinct functional profiles with aviremic HIV infection and aging

Abstract Populations of gamma delta T cells exert different effector function profiles (inflammatory (Th1/Th17) vs. immunoregulatory (Th2/Treg)) in response to non-antigen specific signals in a microenvironment. The nature of gamma delta T cell lineage commitment versus functional capacity at the single cell level is unclear. Also, gamma delta T cells are implicated as drivers of the chronic inflammation found with normal aging and ART-suppressed HIV infection; however, the precise subsets involved in this phenomenon are currently unknown. To address these questions, we optimized a 31-color Intracellular Cytokine Staining (ICS) panel enabling measurement of 10 cytokines, as well as Ki67, granzyme B, and CD107a for use with PBMC from participants of a HIV and Aging cohort. Multi-variate analysis (opt-SNE) of the collected dataset revealed striking differences in the overall functional potential of the V delta 1 (Vδ1) and V delta 2 (Vδ2) subsets, with many Vδ1+ cells not producing any of the cytokines measured. Distinct differences of both the Vδ1+ and Vδ2+ subsets were found between the HIV infected and age-stratified subject groups. Individual gamma delta T cells with a ‘Th0’ phenotype, producing both Th1 and Th2 lineage cytokines, were present in both Vδ1+ and Vδ2+ subsets. Also, HIV+ subjects lacked Vδ2+ cells expressing CD107a, indicating a specific defect in the cytotoxic function of this subset with HIV infection. Further investigation of gamma delta T cell functions and phenotypes could provide new insight into the biology of this unique T cell population and reveal novel therapeutic targets. Supported by a grant from NIH (R01AG060890-01)

Abstract 1261: Mutant IDH-mediated suppression of the Th17 lineage in glioma: Biologic impact and therapeutic potential

Abstract Great excitement has been generated around the identification of tumor-specific hotspot mutations in isocitrate dehydrogenase I (IDH1) as they are the first potential therapeutic targets of low grade gliomas that have been identified in the last several decades. With a low number of viable therapeutic targets, mutations in IDH1 represent new hope in treating these devastating tumors that are invariably recurrent and confer a dismal prognosis in their most aggressive forms. In addition to their high frequency of mutation in gliomas, mutations in IDH1 are tumor-specific suggesting their effective targeting can reduce the collateral damage to the normal brain imparted by standard therapies. Furthermore, mutations in IDH1 lead to the overproduction of the oncometabolite D-2-hydroxyglutarate (D-2HG), which mediates many of mutant IDH1’s effects including blocks to normal differentiation, aberrant histone and DNA methylation profiles, perturbed metabolism, induction of an immunosuppressive microenvironment, among others. To gain an understanding of mutant IDH-mediated tumorigenesis, we generated genetically faithful mouse models of glioma that harbor the pathognomonic signature including the IDH1-R132H mutation and p53 deletion. This orthotopic intracranial injection model generates tumors that overproduce D-2HG, are histologically diffuse, and confer a prolonged survival compared to their wildtype counterparts. Additionally, these models display the proneural glioma subtype and are enriched for an oligodendrocyte precursor cell gene expression signature, both of which are typified by IDH mutations in human glioma. Exploring the impact of the IDH mutation on the tumor microenvironment, we identified several diminished immune cell subsets among the mutant IDH murine tumors, including plasma cells, NK cells, monocytes, and M2 macrophages, while a subtle increase among dendritic cells was observed as indicated through immune deconvolution of RNAseq data of murine brain tumors. Further analysis showed a reduced Th17 gene expression profile that was corroborated through in vitro studies showing a D-2HG-mediated suppression of IL17 producing Th17 cells and a perturbed metabolic activity skewing towards oxidative phosphorylation. Th17 cells have only relatively recently been identified and their biological impact appears to be cancer-context dependent with only a few studies being performed in gliomas. With the potential for Th17-mediated anti-tumor activity, as observed in cases of melanoma, the prospect for understanding this understudied lineage and exposing a new therapeutic avenue is exciting. As such, the biological significance of D-2HG-mediated Th17 suppression, the underlying mechanism, as well as the therapeutic potential and anti-tumor activity of Th17 restoration or IL17 overproduction are actively being investigated. Citation Format: Nathan M. Reynolds, Ashleigh J. Soedel, Ximena Bustamante-Marin, Emily Z. Miller, Paula K. Greer, David M. Ashley, Yiping He, Matthew S. Waitkus, Christopher J. Pirozzi. Mutant IDH-mediated suppression of the Th17 lineage in glioma: Biologic impact and therapeutic potential [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1261.

Review on host-pathogen interaction in dermatophyte infections.

Dermatophytosis is a common superficial fungal infection of the skin and its appendages caused by dermatophytes. Recent times have witnessed a dynamic evolution of dermatophytes driven by their ecology, reproduction, pathogenicity and host immune response, influenced by population migration and socioeconomic status. Dermatophytes establish infection following successful adherence of arthroconidia to the surface of keratinized tissues. The proteolytic enzymes released during adherence and invasion not only ascertain their survival but also allow the persistence of infection in the host. While the cutaneous immune surveillance mechanism, after antigen exposure and presentation, leads to activation of T lymphocytes and subsequent clonal expansion generating effector T cells that differentially polarize to a predominant Th17 response, the response fails to eliminate the pathogen despite the presence of high levels of IFN-γ. In chronic dermatophytosis, antigens are a constant source of stimulus promoting a dysregulated Th17 response causing inflammation. The host-derived iTreg response fails to counterbalance the inflammation and instead polarizes to Th17 lineage, aggravating the chronicity of the infection. Increasing antifungal resistance and recalcitrant dermatophytosis has impeded the overall clinical remission. Human genetic research has the potential to generate knowledge to explore new therapeutic targets. The review focuses on understanding specific virulence factors involved in pathogenesis and defining the role of dysregulated host immune response against chronic dermatophytic infections for future management strategies.

Transcriptional inhibition of STAT1 functions in the nucleus alleviates Th1 and Th17 cell-mediated inflammatory diseases.

T helper 1 cells (Th1 cells) and T helper 17 cells (Th17 cells) play pivotal roles in the pathogenesis of various autoimmune diseases, including psoriasis and inflammatory bowel disease (IBD). Signal transducer and activator of transcription 1 (STAT1) regulates the Th1 and Th17 cell lineage commitment at an early stage and maintains their immunological functions in vitro and in vivo. The previous strategies to block STAT1 functions to treat autoimmune diseases inhibit Th1 cell activity but simultaneously cause hyper-activation of Th17 cells. Herein, to modulate the functions of pathogenic Th1 and Th17 cells without genetic modification in normal physiological conditions, we generated the nucleus-deliverable form of the transcription modulation domain of STAT1 (ndSTAT1-TMD), which can be transduced into the nucleus of the target cells in a dose- and time-dependent manner without affecting the cell viability and T cell activation signaling events. ndSTAT1-TMD significantly blocked the differentiation of naïve CD4+ T cells into Th1 or Th17 cells via competitive inhibition of endogenous STAT1-mediated transcription, which did not influence Th2 and Treg cell differentiation. When the gene expression profile of Th1 or Th17 cells after ndSTAT1-TMD treatment was analyzed by mRNA sequencing, the expression of the genes involved in the differentiation capacity and the immunological functions of Th1 or Th17 cells were substantially reduced. The therapeutic potential of ndSTAT1-TMD was tested in the animal model of psoriasis and colitis, whose pathogenesis is mainly contributed by Th1 or/and Th17 cells. The symptoms and progression of psoriasis and colitis were significantly alleviated by ndSTAT1-TMD treatment, comparable to anti-IL-17A antibody treatment. In conclusion, our study demonstrates that ndSTAT1-TMD can be a new therapeutic reagent for Th1/17 cell-mediated autoimmune diseases by modulating the functions of pathogenic Th1 and Th17 cells together.

Transcription factor RORα enforces stability of the Th17 cell effector program by binding to a Rorc cis-regulatory element.

T helper 17 (Th17) cells regulate mucosal barrier defenses but also promote multiple autoinflammatory diseases. Although many molecular determinants of Th17 cell differentiation have been elucidated, the transcriptional programs that sustain Th17 cells invivo remain obscure. The transcription factor RORγt is critical for Th17 cell differentiation; however, it is not clear whether the closely related RORα, which is co-expressed in Th17 cells, has a distinct role. Here, we demonstrated that although dispensable for Th17 cell differentiation, RORα was necessary for optimal Th17 responses in peripheral tissues. The absence of RORα in Tcells led to reductions in both RORγt expression and effector function among Th17 cells. Cooperative binding of RORα and RORγt to a previously unidentified Rorc cis-regulatory element was essential for Th17 lineage maintenance invivo. These data point to a non-redundant role of RORα in Th17 lineage maintenance via reinforcement of the RORγt transcriptional program.

David John Austin

Differentiation of naive CD4⁺ cells into Th2 cells is accompanied by chromatin remodeling at the Th2 cytokine locus allowing the expression of the IL-4, IL-5, and IL-13 genes. In this...

Insights from DOCK2 in cell function and pathophysiology.

Dedicator of cytokinesis 2 (DOCK2) can activate the downstream small G protein Rac and regulate cytoskeletal reorganization. DOCK2 is essential for critical physiological processes such as migration, activation, proliferation, and effects of immune cells, including lymphocytes, neutrophils, macrophages, and dendritic cells. For example, DOCK2 is involved in the development and activation of T and B lymphocytes by affecting synapse formation and inhibiting the development of the Th2 lineage by downregulating IL-4Rα surface expression. Not only that, DOCK2 may be a molecular target for controlling cardiac transplant rejection and Alzheimer’s disease (AD). Patients with defects in the DOCK2 gene also exhibit a variety of impaired cellular functions, such as chemotactic responses of lymphocytes and reactive oxygen species (ROS) production by neutrophils. To date, DOCK2 has been shown to be involved in the development of various diseases, including AD, pneumonia, myocarditis, colitis, tumors, etc. DOCK2 plays different roles in these diseases and the degree of inflammatory response has a different impact on the progression of disease. In this paper, we present a review of recent advances in the function of DOCK2 in various immune cells and its role in various diseases.

CD103 and periplakin are potential biomarkers for response of metastatic melanoma to pembrolizumab.

This study was designed to screen for preliminary evidence of predictive markers of melanoma response to PD-1 blockade. We hypothesized that the following immune markers would be positive predictors of response: increased densities of CD103 + CD8 + T cells or Th1 lineage T-bet + T cells, high expression of CXCL9-11 and presence of tertiary lymphoid structures. Conversely, we hypothesized that the high expression of barrier molecules would be a negative predictor of response. Patients with advanced melanoma treated with pembrolizumab were identified, and clinical response as well as overall survival data were collected. Tumor samples were evaluated by multiplex immunofluorescence histology. All statistical analyses were performed in R Studio and Microsoft Excel using the Mann-Whitney U test, chi-square test, Spearman's rank correlation and Kaplan-Meier survival curves. Sixty-five advanced melanoma patients were identified, of whom 46 met inclusion criteria and were included in this study. Increased densities ( P = 0.04) and proportions ( P = 0.02) of CD8 + T cells expressing CD103 + were associated with complete response (CR) to pembrolizumab. Improved survival was associated with increased proportions of CD8 + cells expressing CD103 ( P = 0.0085) as well as decreased density of periplakin + cells ( P = 0.012) and periplakin + SOX10 + cells ( P = 0.0012). The density and proportion of CD8 + T cells expressing CD103 + positively correlated with PD-L1 expression, though PD-L1 expression was not significantly correlated with outcomes. This screening study found that increased density and proportion of CD8 + T cells expressing CD103 and decreased density of periplakin were associated with positive outcomes in patients with melanoma metastases treated with pembrolizumab and may warrant further study.