The impact of regulatory T cells on the graft-versus-leukemia effect.

Allogeneic Hematopoietic Stem Cell Transplantation (allo-HSCT) is the only curative therapy for many hematologic malignancies, whereby the Graft-versus-Leukemia (GVL) effect plays a pivotal role in controlling relapse. However, the success of GVL is hindered by Graft-versus-Host Disease (GVHD), where donor T cells attack healthy tissues in the recipient. The ability of natural regulatory T cells (Treg) to suppress immune responses has been exploited as a therapeutical option against GVHD. Still, it is crucial to evaluate if the ability of Treg to suppress GVHD does not compromise the benefits of GVL. Initial studies in animal models suggest that Treg can attenuate GVHD while preserving GVL, but results vary according to tumor type. Human trials using Treg as GVHD prophylaxis or treatment show promising results, emphasizing the importance of infusion timing and Treg/Tcon ratios. In this review, we discuss strategies that can be used aiming to enhance GVL post-Treg infusion and the proposed mechanisms for the maintenance of the GVL effect upon the adoptive Treg transfer. In order to optimize the therapeutic outcomes of Treg administration in allo-HSCT, future efforts should focus on refining Treg sources for infusion and evaluating their specificity for antigens mediating GVHD while preserving GVL responses.

Anti-CX3CL1 (fractalkine) monoclonal antibody attenuates lung and skin fibrosis in sclerodermatous graft-versus-host disease mouse model.

BACKGROUND: Systemic sclerosis (SSc) is an autoimmune disease characterized by vascular injury and inflammation, followed by excessive fibrosis of the skin and other internal organs, including the lungs. CX3CL1 (fractalkine), a chemokine expressed on endothelial cells, supports the migration of macrophages and T cells that express its specific receptor CX3CR1 into targeted tissues. We previously reported that anti-CX3CL1 monoclonal antibody (mAb) treatment significantly inhibited transforming growth factor (TGF)-ß1-induced expression of type I collagen and fibronectin 1 in human dermal fibroblasts. Additionally, anti-mouse CX3CL1 mAb efficiently suppressed skin inflammation and fibrosis in bleomycin- and growth factor-induced SSc mouse models. However, further studies using different mouse models of the complex immunopathology of SSc are required before the initiation of a clinical trial of CX3CL1 inhibitors for human SSc. METHODS: To assess the preclinical utility and functional mechanism of anti-CX3CL1 mAb therapy in skin and lung fibrosis, a sclerodermatous chronic graft-versus-host disease (Scl-cGVHD) mouse model was analyzed with immunohistochemical staining for characteristic infiltrating cells and RNA sequencing assays. RESULTS: On day 42 after bone marrow transplantation, Scl-cGVHD mice showed increased serum CX3CL1 level. Intraperitoneal administration of anti-CX3CL1 mAb inhibited the development of fibrosis in the skin and lungs of Scl-cGVHD model, and did not result in any apparent adverse events. The therapeutic effects were correlated with the number of tissue-infiltrating inflammatory cells and α-smooth muscle actin (α-SMA)-positive myofibroblasts. RNA sequencing analysis of the fibrotic skin demonstrated that cGVHD-dependent induction of gene sets associated with macrophage-related inflammation and fibrosis was significantly downregulated by mAb treatment. In the process of fibrosis, mAb treatment reduced cGVHD-induced infiltration of macrophages and T cells in the skin and lungs, especially those expressing CX3CR1. CONCLUSIONS: Together with our previous findings in other SSc mouse models, the current results indicated that anti-CX3CL1 mAb therapy could be a rational therapeutic approach for fibrotic disorders, such as human SSc and Scl-cGVHD.

The predictive value of T-cell chimerism for disease relapse after allogeneic hematopoietic stem cell transplantation.

Introduction: Chimerism is closely correlated with disease relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, chimerism rate is dynamic changes, and the sensitivity of different chimerism requires further research. Methods: To investigate the predictive value of distinct chimerism for relapse, we measured bone marrow (BM), peripheral blood (PB), and T-cell (isolated from BM) chimerism in 178 patients after allo-HSCT. Results: Receiver operating characteristic (ROC) curve showed that T-cell chimerism was more suitable to predict relapse after allo-HSCT compared with PB and BM chimerism. The cutoff value of T-cell chimerism for predicting relapse was 99.45%. Leukemia and myelodysplastic syndrome (MDS) relapse patients' T-cell chimerism was a gradual decline from 2 months to 9 months after allo-HSCT. Higher risk of relapse and death within 1 year after allo-HSCT. The T-cell chimerism rates in remission and relapse patients were 99.43% and 94.28% at 3 months after allo-HSCT (P = 0.009), 99.31% and 95.27% at 6 months after allo-HSCT (P = 0.013), and 99.26% and 91.32% at 9 months after allo-HSCT (P = 0.024), respectively. There was a significant difference (P = 0.036) for T-cell chimerism between early relapse (relapse within 9 months after allo-HSCT) and late relapse (relapse after 9 months after allo-HSCT) at 2 months after allo-HSCT. Every 1% increase in T-cell chimerism, the hazard ratio for disease relapse was 0.967 (95% CI: 0.948-0.987, P<0.001). Discussion: We recommend constant monitoring T-cell chimerism at 2, 3, 6, and 9 months after allo-HSCT to predict relapse.

[Evidence of GVHD/GVL in allogeneic hematopoietic stem cell transplantation from sex-mismatched donors].

Hematopoietic cell transplantation (HCT) is considered a curative treatment for hematological malignancies. However, HCT recipients often face complications such as graft-versus-host disease (GVHD) and disease relapse. Clinical factors like age and HLA disparity are recognized as risks for GVHD. Notably, sex-mismatched HCT, particularly with female donors and male recipients (F→M), is reported to increase the risk of chronic GVHD. This adverse effect of F→M HCT is thought to result from allogeneic immune response against minor histocompatibility antigens encoded on the Y-chromosome of a male recipient (HY-antigens). Indeed, antibodies against HY-antigens (HY-Abs) were detected three months after F→M HCT, and the cumulative number of HY-Abs was significantly associated with increased risks of chronic GVHD and non-relapse mortality. This review focuses on F→M HCT, shedding light on its impact in several clinical settings and presenting clinical evidence of its allogeneic response, encompassing GVHD and graft-versus-leukemia (GVL) effects. Additionally, potential clinical options to mitigate adverse effects in F→M HCT will be discussed. Further investigation is required to improve clinical outcomes and understand allogenic immunological reconstitution after F→M HCT.

The Confounding Role of Graft-Versus-Host Disease in Animal Models of Cancer Immunotherapy: A Systematic Review.

BACKGROUND: Cancer immunotherapy has emerged as a transformative approach for treating various malignancies, including melanoma, lung cancer, breast cancer, and leukemia. Animal models have been instrumental in elucidating the mechanisms and potential of these therapies. However, graft-versus-host disease (GVHD) is an inherent challenge in these studies, primarily because the introduction of foreign immune cells or tissues often triggers immune responses. METHODS: A detailed systematic search was conducted across various scientific databases, including PubMed, Scopus, Embase, and Web of Science. The search aimed to identify peer-reviewed articles published in English from January 2000 to September 2023. Keywords and phrases used in the search included "Graft-versus-Host Disease", "GVHD", "animal models", "cancer immunotherapy", and combinations thereof. Boolean operators (AND/OR) were employed to refine the search. Finally, 6 articles were included in this systematic review, which is registered on PROSPERO (ID number CRD42024488544). RESULTS: Our systematic review identified several mechanisms employed in animal studies to mitigate the confounding effects of GVHD. These included genetically modified mouse models, immunosuppressive drugs, and humanized mice. Furthermore, the review highlights innovative approaches such as selective T-cell depletion and the use of specific cytokine inhibitors. CONCLUSION: By systematically identifying and mitigating the confounding effects of GVHD, we can significantly improve the predictive validity of preclinical trials, obtain broadly applicable findings, improve the efficiency of drugs, enhance safety profiling, and develop better therapeutic strategies. This approach is crucial in ensuring that the immunotherapeutic strategies developed in the laboratory are reflective of the human physiological response, thereby bridging a critical translational gap in oncological research.

γδ T cells in oral diseases.

OBJECTIVE: γδ T cells are a distinct subset of unconventional T cells, which link innate and adaptive immunity by secreting cytokines and interacting with other immune cells, thereby modulating immune responses. As the first line of host defense, γδ T cells are essential for mucosal homeostasis and immune surveillance. When abnormally activated or impaired, γδ T cells can contribute to pathogenic processes. Accumulating evidence has revealed substantial impacts of γδ T cells on the pathogenesis of cancers, infections, and immune-inflammatory diseases. γδ T cells exhibit dual roles in cancers, promoting or inhibiting tumor growth, depending on their phenotypes and the clinical stage of cancers. During infections, γδ T cells exert high cytotoxic activity in infectious diseases, which is essential for combating bacterial and viral infections by recognizing foreign antigens and activating other immune cells. γδ T cells are also implicated in the onset and progression of immune-inflammatory diseases. However, the specific involvement and underlying mechanisms of γδ T cells in oral diseases have not been systematically discussed. METHODS: We conducted a systematic literature review using the PubMed/MEDLINE databases to identify and analyze relevant literature on the roles of γδ T cells in oral diseases. RESULTS: The literature review revealed that γδ T cells play a pivotal role in maintaining oral mucosal homeostasis and are involved in the pathogenesis of oral cancers, periodontal diseases, graft-versus-host disease (GVHD), oral lichen planus (OLP), and oral candidiasis. γδ T cells mainly influence various pathophysiological processes, such as anti-tumor activity, eradication of infection, and immune response regulation. CONCLUSION: This review focuses on the involvement of γδ T cells in oral diseases, with a particular emphasis on the main functions and underlying mechanisms by which γδ T cells influence the pathogenesis and progression of these conditions. This review underscores the potential of γδ T cells as therapeutic targets in managing oral health issues.

Human Herpes Virus-6 (HHV-6) Reactivation after Hematopoietic Cell Transplant and Chimeric Antigen Receptor (CAR)- T Cell Therapy: A Shifting Landscape.

HHV-6B reactivation affects approximately half of all allogeneic hematopoietic cell transplant (HCT) recipients. HHV-6B is the most frequent infectious cause of encephalitis following HCT and is associated with pleiotropic manifestations in this setting, including graft-versus-host disease, myelosuppression, pneumonitis, and CMV reactivation, although the causal link is not always clear. When the virus inserts its genome in chromosomes of germ cells, the chromosomally integrated form (ciHHV6) is inherited by offspring. The condition of ciHHV6 is characterized by the persistent detection of HHV-6 DNA, often confounding diagnosis of reactivation and disease-this has also been associated with adverse outcomes. Recent changes in clinical practice in the field of cellular therapies, including a wider use of post-HCT cyclophosphamide, the advent of letermovir for CMV prophylaxis, and the rapid expansion of novel cellular therapies require contemporary epidemiological studies to determine the pathogenic role and spectrum of disease of HHV-6B in the current era. Research into the epidemiology and clinical significance of HHV-6B in chimeric antigen receptor T cell (CAR-T cell) therapy recipients is in its infancy. No controlled trials have determined the optimal treatment for HHV-6B. Treatment is reserved for end-organ disease, and the choice of antiviral agent is influenced by expected toxicities. Virus-specific T cells may provide a novel, less toxic therapeutic modality but is more logistically challenging. Preventive strategies are hindered by the high toxicity of current antivirals. Ongoing study is needed to keep up with the evolving epidemiology and impact of HHV-6 in diverse and expanding immunocompromised patient populations.

Mesenchymal stromal cells with chimaeric antigen receptors for enhanced immunosuppression.

Allogeneic mesenchymal stromal cells (MSCs) are a safe treatment option for many disorders of the immune system. However, clinical trials using MSCs have shown inconsistent therapeutic efficacy, mostly owing to MSCs providing insufficient immunosuppression in target tissues. Here we show that antigen-specific immunosuppression can be enhanced by genetically modifying MSCs with chimaeric antigen receptors (CARs), as we show for E-cadherin-targeted CAR-MSCs for the treatment of graft-versus-host disease in mice. CAR-MSCs led to superior T-cell suppression and localization to E-cadherin+ colonic cells, ameliorating the animals' symptoms and survival rates. On antigen-specific stimulation, CAR-MSCs upregulated the expression of immunosuppressive genes and receptors for T-cell inhibition as well as the production of immunosuppressive cytokines while maintaining their stem cell phenotype and safety profile in the animal models. CAR-MSCs may represent a widely applicable therapeutic technology for enhancing immunosuppression.

Long-Term Clinical Outcomes and B Cell Immune Reconstitution Following Allo-HCT With Prophylactic, Post-Transplant Rituximab.

Chronic graft-versus-host disease (cGVHD) remains a significant source of morbidity and mortality following allogeneic hematopoietic cell transplantation (HCT). Post-transplant, prophylactic rituximab has successfully decreased cGHVD rates in clinical trials, but the durability of this strategy is uncertain. The long-terms effect of post-HCT B cell depletion on immune reconstitution, B cell function, and infectious complications are also unknown. In this study, we provide 10 yr follow-up and correlative analyses on patients given post-HCT, prophylactic rituximab. The objective of the study is to examine the durability of cGVHD protection as well as the long-term effect of rituximab prophylaxis on protective immune reconstitution, B cell function, and alloantibody formation. We analyzed 35 patients given prophylactic rituximab on phase II clinical trial. Clinical outcomes included cGVHD development, relapse and survival outcomes, and infectious outcomes. Correlative analyses included B cell subset analysis, development of antibodies to infectious antigens, and, for male patients receiving female donor grafts, development of antibodies to HY antigens. To further investigate the effect of rituximab on immune reconstitution and function, we also analyzed 43 similarly transplanted patients who did not receive post- or peri-HCT rituximab as a comparator group. For patients who received rituximab, the 8-yr cumulative incidence of cGHVD and freedom from immunosuppression were 20.0% and 76.2%, respectively. Importantly, no late incidences of cGVHD developed beyond 14 mo post-HCT. Relative to patients who did not receive rituximab, post-HCT rituximab was associated with increased B cell aplasia at 1 yr post-HCT (42.9% versus 11% of patients, P = .037); by 3 yr post-HCT, this aplasia resolved. Patients who received rituximab also had a significantly lower proportion of IgD+/CD38+ transitional B cells at 3 yr post-HCT (78.8% versus 89.9%, P = .039); at 10 yr post-HCT, this percentage remained markedly decreased at 50.7%. Rituximab prophylaxis altered B cell function. In male patients receiving female donor grafts, fewer patients developed HY antibodies at 3 yr post-HCT (20% versus 78%, P = .04). At 10 yr post-HCT, HY antibody production remained decreased at 33%. Rituximab prophylaxis was also associated with significantly lower antibody response to tetanus and EBV infectious antigens as well as lower IgG levels. Despite these changes, post-HCT was not associated with increased infections, although patients who received rituximab required intravenous immunoglobulin (IVIG) supplementation more frequently than those who did not (62.9% versus 32.6% of patients, P = .01). Prior data on the efficacy and feasibility of rituximab prophylaxis are durable, with persistent reduction in cGVHD. Rituximab prophylaxis also results in lasting B cell immunologic changes, with altered B cell subset composition and decreased alloantibody formation. Associated infectious risks were not increased, perhaps mitigated by high IVIG use.

HLA peptide-binding pocket diversity modulates immunological complications after cord blood transplant in acute leukaemia.

Pocket motifs and their amino acid positions of HLA molecules are known to govern antigen presentation to effector cells. Our objective was to analyse their influence on the risk of graft-versus-host disease (GVHD) and relapse after umbilical cord blood transplant (UCBT). The transplant characteristics of 849 patients with acute leukaemia were obtained from the Eurocord/EBMT database. Higher acute (a) GVHD was associated with homozygosity of UCB HLA-C amino acid positions 77 and 80 (NN/KK) (p = 0.008). Severe aGVHD was associated with HLA-A pocket B YSAVMENVHY motif (p = 0.002) and NN and RR genotypes of the HLA-C amino acid positions 77 and 156 (p = 0.006 and p = 0.002). Such risk was also increased in case of recipient and UCB mismatches in P4 (p < 0.0001) and P9 (p = 0.003) pockets of HLA-DQB1 alleles. For chronic GVHD, the pocket B YYAVMEISNY motif of the HLA-B*15:01 allele and the absence of mismatch between recipient and UCB in the P6 pocket of HLA-DRB1 were associated with a lower risk (p = 0.0007 and p = 0.0004). In relapse, both UCB pocket B YFAVMENVHY belonging to HLA-A*32:01 and recipient pocket B YDSVGENYQY motif of the HLA-C*07:01 allele were associated with higher risk (p = 0.0026 and p = 0.015). We provide clues on HLA-mediated cellular interactions and their role in the development of GVHD and relapse.

Blood and guts: how the intestinal microbiome shapes hematopoiesis and treatment of hematologic disease.

ABSTRACT: Over the past 10 years, there has been a marked increase in recognition of the interplay between the intestinal microbiome and the hematopoietic system. Despite their apparent distance in the body, a large literature now supports the relevance of the normal intestinal microbiota to steady-state blood production, affecting both hematopoietic stem and progenitor cells as well as differentiated immune cells. Microbial metabolites enter the circulation where they can trigger cytokine signaling that influences hematopoiesis. Furthermore, the state of the microbiome is now recognized to affect outcomes from hematopoietic stem cell transplant, immunotherapy, and cellular therapies for hematologic malignancies. Here we review the mechanisms by which microbiotas influence hematopoiesis in development and adulthood as well as the avenues by which microbiotas are thought to impact stem cell transplant engraftment, graft-versus-host disease, and efficacy of cell and immunotherapies. We highlight areas of future research that may lead to reduced adverse effects of antibiotic use and improved outcomes for patients with hematologic conditions.

The chemerin/CMKLR1 axis regulates intestinal graft-versus-host disease.

Gastrointestinal graft-versus-host disease (GvHD) is a major cause of mortality and morbidity following allogeneic bone marrow transplantation (allo-BMT). Chemerin is a chemotactic protein that recruits leukocytes to inflamed tissues by interacting with ChemR23/CMKLR1, a chemotactic receptor expressed by leukocytes, including macrophages. During acute GvHD, chemerin plasma levels were strongly increased in allo-BM-transplanted mice. The role of the chemerin/CMKLR1 axis in GvHD was investigated using Cmklr1-KO mice. WT mice transplanted with an allogeneic graft from Cmklr1-KO donors (t-KO) had worse survival and more severe GvHD. Histological analysis demonstrated that the gastrointestinal tract was the organ mostly affected by GvHD in t-KO mice. The severe colitis of t-KO mice was characterized by massive neutrophil infiltration and tissue damage associated with bacterial translocation and exacerbated inflammation. Similarly, Cmklr1-KO recipient mice showed increased intestinal pathology in both allogeneic transplant and dextran sulfate sodium-induced colitis. Notably, the adoptive transfer of WT monocytes into t-KO mice mitigated GvHD manifestations by decreasing gut inflammation and T cell activation. In patients, higher chemerin serum levels were predictive of GvHD development. Overall, these results suggest that CMKLR1/chemerin may be a protective pathway for the control of intestinal inflammation and tissue damage in GvHD.

Shared graft-versus-leukemia minor histocompatibility antigens in DISCOVeRY-BMT.

T-cell responses to minor histocompatibility antigens (mHAs) mediate graft-versus-leukemia (GVL) effects and graft-versus-host disease (GVHD) in allogeneic hematopoietic cell transplantation. Therapies that boost T-cell responses improve allogeneic hematopoietic cell transplant (alloHCT) efficacy but are limited by concurrent increases in the incidence and severity of GVHD. mHAs with expression restricted to hematopoietic tissue (GVL mHAs) are attractive targets for driving GVL without causing GVHD. Prior work to identify mHAs has focused on a small set of mHAs or population-level single-nucleotide polymorphism-association studies. We report the discovery of a large set of novel GVL mHAs based on predicted immunogenicity, tissue expression, and degree of sharing among donor-recipient pairs (DRPs) in the DISCOVeRY-BMT data set of 3231 alloHCT DRPs. The total number of predicted mHAs varied by HLA allele, and the total number and number of each class of mHA significantly differed by recipient genomic ancestry group. From the pool of predicted mHAs, we identified the smallest sets of GVL mHAs needed to cover 100% of DRPs with a given HLA allele. We used mass spectrometry to search for high-population frequency mHAs for 3 common HLA alleles. We validated 24 predicted novel GVL mHAs that are found cumulatively within 98.8%, 60.7%, and 78.9% of DRPs within DISCOVeRY-BMT that express HLA-A∗02:01, HLA-B∗35:01, and HLA-C∗07:02, respectively. We confirmed the immunogenicity of an example novel mHA via T-cell coculture with peptide-pulsed dendritic cells. This work demonstrates that the identification of shared mHAs is a feasible and promising technique for expanding mHA-targeting immunotherapeutics.

IL-34 deficiency impairs FOXP3+ Treg function in a model of autoimmune colitis and decreases immune tolerance homeostasis.

BACKGROUND: Immune homeostasis requires fully functional Tregs with a stable phenotype to control autoimmunity. Although IL-34 is a cytokine first described as mainly involved in monocyte cell survival and differentiation, we recently described its expression by CD8+ Tregs in a rat model of transplantation tolerance and by activated FOXP3+ CD4+ and CD8+ Tregs in human healthy individuals. However, its role in autoimmunity and potential in human diseases remains to be determined. METHODS: We generated Il34-/- rats and using both Il34-/- rats and mice, we investigated their phenotype under inflammatory conditions. Using Il34-/- rats, we further analyzed the impact of the absence of expression of IL-34 for CD4+ Tregs suppressive function. We investigated the potential of IL-34 in human disease to prevent xenogeneic GVHD and human skin allograft rejection in immune humanized immunodeficient NSG mice. Finally, taking advantage of a biocollection, we investigated the correlation between presence of IL-34 in the serum and kidney transplant rejection. RESULTS: Here we report that the absence of expression of IL-34 in Il34-/- rats and mice leads to an unstable immune phenotype, with production of multiple auto-antibodies, exacerbated under inflammatory conditions with increased susceptibility to DSS- and TNBS-colitis in Il34-/- animals. Moreover, we revealed the striking inability of Il34-/- CD4+ Tregs to protect Il2rg-/- rats from a wasting disease induced by transfer of pathogenic cells, in contrast to Il34+/+ CD4+ Tregs. We also showed that IL-34 treatment delayed EAE in mice as well as GVHD and human skin allograft rejection in immune humanized immunodeficient NSG mice. Finally, we show that presence of IL-34 in the serum is associated with a longer rejection-free period in kidney transplanted patients. CONCLUSION: Altogether, our data emphasize on the crucial necessity of IL-34 for immune homeostasis and for CD4+ Tregs suppressive function. Our data also shows the therapeutic potential of IL-34 in human transplantation and auto-immunity. HIGHLIGHTS: -Absence of expression of IL-34 in Il34-/- rats and mice leads to an unstable immune phenotype, with a production of multiple auto-antibodies and exacerbated immune pathology under inflammatory conditions. -Il34-/- CD4+ Tregs are unable to protect Il2rg-/- rats from colitis induced by transfer of pathogenic cells. -IL-34 treatment delayed EAE in mice, as well as acute GVHD and human skin allograft rejection in immune-humanized immunodeficient NSG mice.

Contribution of Dendritic Cell Subsets to T Cell-Dependent Responses in Mice.

BATF3-deficient mice that lack CD8+ dendritic cells (DCs) showed an exacerbation of chronic graft-versus-host disease (cGVHD), including T follicular helper (Tfh) cell and autoantibody responses, whereas mice carrying the Sle2c2 lupus-suppressive locus with a mutation in the G-CSFR showed an expansion of CD8+ DCs and a poor mobilization of plasmacytoid DCs (pDCs) and responded poorly to cGVHD induction. Here, we investigated the contribution of CD8+ DCs and pDCs to the humoral response to protein immunization, where CD8neg DCs are thought to represent the major inducers. Both BATF3-/- and Sle2c2 mice had reduced humoral and germinal center (GC) responses compared with C57BL/6 (B6) controls. We showed that B6-derived CD4+ DCs are the major early producers of IL-6, followed by CD4-CD8- DCs. Surprisingly, IL-6 production and CD80 expression also increased in CD8+ DCs after immunization, and B6-derived CD8+ DCs rescued Ag-specific adaptive responses in BATF3-/- mice. In addition, inflammatory pDCs (ipDCs) produced more IL-6 than all conventional DCs combined. Interestingly, G-CSFR is highly expressed on pDCs. G-CSF expanded pDC and CD8+ DC numbers and IL-6 production by ipDCs and CD4+ DCs, and it improved the quality of Ab response, increasing the localization of Ag-specific T cells to the GC. Finally, G-CSF activated STAT3 in early G-CSFR+ common lymphoid progenitors of cDCs/pDCs but not in mature cells. In conclusion, we showed a multilayered role of DC subsets in priming Tfh cells in protein immunization, and we unveiled the importance of G-CSFR signaling in the development and function pDCs.

microRNA-142 guards against autoimmunity by controlling Treg cell homeostasis and function.

Regulatory T (Treg) cells are critical in preventing aberrant immune responses. Posttranscriptional control of gene expression by microRNA (miRNA) has recently emerged as an essential genetic element for Treg cell function. Here, we report that mice with Treg cell-specific ablation of miR-142 (hereafter Foxp3CremiR-142fl/fl mice) developed a fatal systemic autoimmune disorder due to a breakdown in peripheral T-cell tolerance. Foxp3CremiR-142fl/fl mice displayed a significant decrease in the abundance and suppressive capacity of Treg cells. Expression profiling of miR-142-deficient Treg cells revealed an up-regulation of multiple genes in the interferon gamma (IFNγ) signaling network. We identified several of these IFNγ-associated genes as direct miR-142-3p targets and observed excessive IFNγ production and signaling in miR-142-deficient Treg cells. Ifng ablation rescued the Treg cell homeostatic defect and alleviated development of autoimmunity in Foxp3CremiR-142fl/fl mice. Thus, our findings implicate miR-142 as an indispensable regulator of Treg cell homeostasis that exerts its function by attenuating IFNγ responses.

Resolution of Inflammation in Acute Graft-Versus-Host-Disease: Advances and Perspectives.

Inflammation is an essential reaction of the immune system to infections and sterile tissue injury. However, uncontrolled or unresolved inflammation can cause tissue damage and contribute to the pathogenesis of various inflammatory diseases. Resolution of inflammation is driven by endogenous molecules, known as pro-resolving mediators, that contribute to dampening inflammatory responses, promoting the resolution of inflammation and the recovery of tissue homeostasis. These mediators have been shown to be useful to decrease inflammatory responses and tissue damage in various models of inflammatory diseases. Graft-versus-host disease (GVHD) is a major unwanted reaction following allogeneic hematopoietic stem cell transplantation (allo-HSCT) and is characterized by an exacerbated inflammatory response provoked by antigen disparities between transplant recipient and donor. There is no fully effective treatment or prophylaxis for GVHD. This review explores the effects of several pro-resolving mediators and discusses their potential use as novel therapies in the context of GVHD.

Human skin-resident host T cells can persist long term after allogeneic stem cell transplantation and maintain recirculation potential.

Tissue-resident memory T cells (TRM) have recently emerged as crucial cellular players for host defense in a wide variety of tissues and barrier sites. Insights into the maintenance and regulatory checkpoints of human TRM cells remain scarce, especially due to the difficulties associated with tracking T cells through time and space in humans. We therefore sought to identify and characterize skin-resident T cells in humans defined by their long-term in situ lodgment. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) preceded by myeloablative chemotherapy unmasked long-term sequestration of host T cell subsets in human skin despite complete donor T cell chimerism in the blood. Single-cell chimerism analysis paired with single-cell transcriptional profiling comprehensively characterized these bona fide long-term skin-resident T cells and revealed differential tissue maintenance for distinct T cell subsets, specific TRM cell markers such as galectin-3, but also tissue exit potential with retention of the transcriptomic TRM cell identity. Analysis of 26 allo-HSCT patients revealed profound interindividual variation in the tissue maintenance of host skin T cells. The long-term persistence of host skin T cells in a subset of these patients did not correlate with the development of chronic GvHD. Our data exemplify the power of exploiting a clinical situation as a proof of concept for the existence of bona fide human skin TRM cells and reveal long-term persistence of host T cells in a peripheral tissue but not in the circulation or bone marrow in a subset of allo-HSCT patients.