From promise to practice: CAR T and Treg cell therapies in autoimmunity and other immune-mediated diseases.

Autoimmune diseases, characterized by the immune system's attack on the body's own tissues, affect millions of people worldwide. Current treatments, which primarily rely on broad immunosuppression and symptom management, are often associated with significant adverse effects and necessitate lifelong therapy. This review explores the next generation of therapies for immune-mediated diseases, including chimeric antigen receptor (CAR) T cell and regulatory T cell (Treg)-based approaches, which offer the prospect of targeted, durable disease remission.

Transcriptional and epigenetic characterization of a new in vitro platform to model the formation of human pharyngeal endoderm.

Background: The Pharyngeal Endoderm (PE) is an extremely relevant developmental tissue, serving as the progenitor for the esophagus, parathyroids, thyroids, lungs, and thymus. While several studies have highlighted the importance of PE cells, a detailed transcriptional and epigenetic characterization of this important developmental stage is still missing, especially in humans, due to technical and ethical constraints pertaining to its early formation.

Results: Here we fill this knowledge gap by developing an in vitro protocol for the derivation of PE-like cells from human Embryonic Stem Cells (hESCs) and by providing an integrated multi-omics characterization.

AML/T cell interactomics uncover correlates of patient outcomes and the key role of ICAM1 in T cell killing of AML.

T cells are important for the control of acute myeloid leukemia (AML), a common and often deadly malignancy. We observed that some AML patient samples are resistant to killing by human-engineered cytotoxic CD4 T cells. Single-cell RNA-seq of primary AML samples and CD4 T cells before and after their interaction uncovered transcriptional programs that correlate with AML sensitivity or resistance to CD4 T cell killing.

Epigenetic signature and key transcriptional regulators of human antigen-specific type 1 regulatory T cells.

Human adaptive immunity is orchestrated by effector and regulatory T (Treg) cells. Natural Tregs arise in the thymus where they are shaped to recognize self-antigens, while type 1 Tregs or Tr1 cells are induced from conventional peripheral CD4 T cells in response to peripheral antigens, such as alloantigens and allergens. Tr1 cells have been developed as a potential therapy for inducing antigen-specific tolerance, because they can be rapidly differentiated in response to a target antigen.

Erratum: knockout-humanized mouse model for pre-clinical safety and efficacy evaluation of Treg-like cell products.

[This corrects the article DOI: 10.1016/j.omtm.

Identification of unstable regulatory and autoreactive effector T cells that are expanded in patients with mutations.

Studies of the monogenic autoimmune disease immunodysregulation polyendocrinopathy enteropathy X-linked syndrome (IPEX) have elucidated the essential function of the transcription factor FOXP3 and thymic-derived regulatory T cells (T) in controlling peripheral tolerance. However, the presence and the source of autoreactive T cells in IPEX remain undetermined. Here, we investigated how FOXP3 deficiency affects the T cell receptor (TCR) repertoire and T stability in vivo and compared T cell abnormalities in patients with IPEX with those in patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (APECED).

IPEX syndrome from diagnosis to cure, learning along the way.

In the past 2 decades, a significant number of studies have been published describing the molecular and clinical aspects of immune dysregulation polyendocrinopathy enteropathy X-linked (IPEX) syndrome. These studies have refined our knowledge of this rare yet prototypic genetic autoimmune disease, advancing the diagnosis, broadening the clinical spectrum, and improving our understanding of the underlying immunologic mechanisms. Despite these advances, Forkhead box P3 mutations have devastating consequences, and treating patients with IPEX syndrome remains a challenge, even with safer strategies for hematopoietic stem cell transplantation and gene therapy becoming a promising reality.

knockout-humanized mouse model for pre-clinical safety and efficacy evaluation of Treg-like cell products.

Forkhead box P3 (FOXP3) is an essential transcription factor for regulatory T cell (Treg) function. Defects in Tregs mediate many immune diseases including the monogenic autoimmune disease immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX), which is caused by mutations. Treg cell products are a promising modality to induce allograft tolerance or reduce the use of immunosuppressive drugs to prevent rejection, as well as in the treatment of acquired autoimmune diseases.

AML/T cell interactomics uncover correlates of patient outcomes and the key role of ICAM1 in T cell killing of AML.

Unlabelled: T cells are important for the control of acute myeloid leukemia (AML), a common and often deadly malignancy. We observed that some AML patient samples are resistant to killing by human engineered cytotoxic CD4 T cells. Single-cell RNA-seq of primary AML samples and CD4 T cells before and after their interaction uncovered transcriptional programs that correlate with AML sensitivity or resistance to CD4 T cell killing.

Type 1 regulatory T cell-mediated tolerance in health and disease.

Type 1 regulatory T (Tr1) cells, in addition to other regulatory cells, contribute to immunological tolerance to prevent autoimmunity and excessive inflammation. Tr1 cells arise in the periphery upon antigen stimulation in the presence of tolerogenic antigen presenting cells and secrete large amounts of the immunosuppressive cytokine IL-10. The protective role of Tr1 cells in autoimmune diseases and inflammatory bowel disease has been well established, and this led to the exploration of this population as a potential cell therapy.

Epigenetic and immunological indicators of IPEX disease in subjects with FOXP3 gene mutation.

Background: Forkhead box protein 3 (FOXP3) is the master transcription factor in CD4CD25CD127 regulatory T (Treg) cells. Mutations in FOXP3 result in IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked) syndrome. Clinical presentation of IPEX syndrome is broader than initially described, challenging the understanding of the disease, its evolution, and treatment choice.

Sequential Stem Cell-Kidney Transplantation in Schimke Immuno-osseous Dysplasia.

Lifelong immunosuppression is required for allograft survival after kidney transplantation but may not ultimately prevent allograft loss resulting from chronic rejection. We developed an approach that attempts to abrogate immune rejection and the need for post-transplantation immunosuppression in three patients with Schimke immuno-osseous dysplasia who had both T-cell immunodeficiency and renal failure. Each patient received sequential transplants of αβ T-cell-depleted and CD19 B-cell-depleted haploidentical hematopoietic stem cells and a kidney from the same donor.

Downregulation of SATB1 by miRNAs reduces megakaryocyte/erythroid progenitor expansion in preclinical models of Diamond-Blackfan anemia.

Diamond-Blackfan Anemia (DBA) is an inherited bone marrow failure syndrome that is associated with anemia, congenital anomalies, and cancer predisposition. It is categorized as a ribosomopathy, because more than 80% or patients have haploinsufficiency of either a small or large subunit-associated ribosomal protein (RP). The erythroid pathology is due predominantly to a block and delay in early committed erythropoiesis with reduced megakaryocyte/erythroid progenitors (MEPs).

The Women of FOCIS: Promoting Equality and Inclusiveness in a Professional Federation of Clinical Immunology Societies.

The authors of this article, all women who have been deeply committed to the Federation of Clinical Immunology Societies (FOCIS), performed a retrospective analysis of gender equality practices of FOCIS to identify areas for improvement and make recommendations accordingly. Gender data were obtained and analyzed for the period from January 2010 to July 2021. Outcome measures included numbers of men and women across the following categories: membership enrollment, meeting and course faculty and attendees, committee and leadership composition.

Co-Expression of FOXP3FL and FOXP3Δ2 Isoforms Is Required for Optimal Treg-Like Cell Phenotypes and Suppressive Function.

FOXP3 is the master transcription factor in both murine and human FOXP3 regulatory T cells (Tregs), a T-cell subset with a central role in controlling immune responses. Loss of the functional Foxp3 protein in mice leads to acute early-onset lethal lymphoproliferation. Similarly, pathogenic FOXP3 mutations in humans lead to immunodysregulation, polyendocrinopathy, enteropathy, and X-linked (IPEX) syndrome, which are characterized by systemic autoimmunity that typically begins in the first year of life.

Alloantigen-specific type 1 regulatory T cells suppress through CTLA-4 and PD-1 pathways and persist long-term in patients.

Type 1 regulatory T (Tr1) cells are inducible, interleukin (IL)-10FOXP3 regulatory T cells that can suppress graft-versus-host disease (GvHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). We have optimized an in vitro protocol to generate a Tr1-enriched cell product called T-allo10, which is undergoing clinical evaluation in patients with hematological malignancies receiving a human leukocyte antigen (HLA)–mismatched allo-HSCT. Donor-derived T-allo10 cells are specific for host alloantigens, are anergic, and mediate alloantigen-specific suppression.

BHLHE40 Regulates IL-10 and IFN- Production in T Cells but Does Not Interfere With Human Type 1 Regulatory T Cell Differentiation.

Type 1 regulatory T (Tr1) cells are subset of peripherally induced antigen-specific regulatory T cells. IL-10 signaling has been shown to be indispensable for polarization and function of Tr1 cells. However, the transcriptional machinery underlying human Tr1 cell differentiation and function is not yet elucidated.

The Yin and Yang of Type 1 Regulatory T Cells: From Discovery to Clinical Application.

Regulatory T cells are essential players of peripheral tolerance and suppression of inflammatory immune responses. Type 1 regulatory T (Tr1) cells are FoxP3 regulatory T cells induced in the periphery under tolerogenic conditions. Tr1 cells are identified as LAG3CD49b mature CD4 T cells that promote peripheral tolerance through secretion of IL-10 and TGF-β in addition to exerting perforin- and granzyme B-mediated cytotoxicity against myeloid cells.

Development of β-globin gene correction in human hematopoietic stem cells as a potential durable treatment for sickle cell disease.

Sickle cell disease (SCD) is the most common serious monogenic disease with 300,000 births annually worldwide. SCD is an autosomal recessive disease resulting from a single point mutation in codon six of the β-globin gene (). Ex vivo β-globin gene correction in autologous patient-derived hematopoietic stem and progenitor cells (HSPCs) may potentially provide a curative treatment for SCD.

Human-engineered Treg-like cells suppress FOXP3-deficient T cells but preserve adaptive immune responses .

Objectives: Genetic or acquired defects in FOXP3 regulatory T cells (Tregs) play a key role in many immune-mediated diseases including immune dysregulation polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. Previously, we demonstrated CD4 T cells from healthy donors and IPEX patients can be converted into functional Treg-like cells by lentiviral transfer of (CD4). These CD4 cells have potent regulatory function, suggesting their potential as an innovative therapeutic.

InsB9-23 Gene Transfer to Hepatocyte-Based Combined Therapy Abrogates Recurrence of Type 1 Diabetes After Islet Transplantation.

The induction of antigen (Ag)-specific tolerance represents a therapeutic option for autoimmune diabetes. We demonstrated that administration of a lentiviral vector enabling expression of insulin B chain 9-23 (InsB9-23) (LV.InsB) in hepatocytes arrests β-cell destruction in prediabetic NOD mice by generating InsB9-23-specific FoxP3 T regulatory cells (Tregs).