Barbara U. Schraml

Bio: Barbara U. Schraml is an academic researcher from Ludwig Maximilian University of Munich. The author has contributed to research in topics: Dendritic cell & Immune system. The author has an hindex of 19, co-authored 34 publications receiving 5116 citations. Previous affiliations of Barbara U. Schraml include London Research Institute & Francis Crick Institute.

Batf3 Deficiency Reveals a Critical Role for CD8α+ Dendritic Cells in Cytotoxic T Cell Immunity

Abstract: Although in vitro observations suggest that cross-presentation of antigens is mediated primarily by CD8α+ dendritic cells, in vivo analysis has been hampered by the lack of systems that selectively eliminate this cell lineage. We show that deletion of the transcription factor Batf3 ablated development of CD8α+ dendritic cells, allowing us to examine their role in immunity in vivo. Dendritic cells from Batf3–/– mice were defective in cross-presentation, and Batf3–/– mice lacked virus-specific CD8+ T cell responses to West Nile virus. Importantly, rejection of highly immunogenic syngeneic tumors was impaired in Batf3–/– mice. These results suggest an important role for CD8α+ dendritic cells and cross-presentation in responses to viruses and in tumor rejection.

Dendritic cells, monocytes and macrophages: a unified nomenclature based on ontogeny

Abstract: The mononuclear phagocyte system (MPS) has historically been categorized into monocytes, dendritic cells and macrophages on the basis of functional and phenotypical characteristics. However, considering that these characteristics are often overlapping, the distinction between and classification of these cell types has been challenging. In this Opinion article, we propose a unified nomenclature for the MPS. We suggest that these cells can be classified primarily by their ontogeny and secondarily by their location, function and phenotype. We believe that this system permits a more robust classification during both steady-state and inflammatory conditions, with the benefit of spanning different tissues and across species.

The AP-1 transcription factor Batf controls TH17 differentiation

Abstract: AP-1 (activator protein-1) transcription factors, also known as JUN factors, are broadly acting factors regulating many inducible genetic responses. Schraml et al. report a surprising mechanism that expands the biological repertoire of the AP-1 family. They find that the AP-1 transcription factor Batf plays a critical role in the differentiation of IL17-producing T-helper cells. TH17 cells comprise a subset of CD4+ T cells that coordinate the inflammatory response in host defence but are pathogenic in autoimmunity. Here, the AP-1 transcription factor BATF is shown to have a critical role in TH17 cell differentiation, with Batf−/− mice displaying a defect in TH17 differentiation and resistance to experimental autoimmune encephalomyelitis. Activator protein 1 (AP-1, also known as JUN) transcription factors are dimers of JUN, FOS, MAF and activating transcription factor (ATF) family proteins characterized by basic region and leucine zipper domains1. Many AP-1 proteins contain defined transcriptional activation domains, but BATF and the closely related BATF3 (refs 2, 3) contain only a basic region and leucine zipper, and are considered to be inhibitors of AP-1 activity3,4,5,6,7,8. Here we show that Batf is required for the differentiation of IL17-producing T helper (TH17) cells9. TH17 cells comprise a CD4+ T-cell subset that coordinates inflammatory responses in host defence but is pathogenic in autoimmunity10,11,12,13. Batf-/- mice have normal TH1 and TH2 differentiation, but show a defect in TH17 differentiation, and are resistant to experimental autoimmune encephalomyelitis. Batf-/- T cells fail to induce known factors required for TH17 differentiation, such as RORγt11 (encoded by Rorc) and the cytokine IL21 (refs 14–17). Neither the addition of IL21 nor the overexpression of RORγt fully restores IL17 production in Batf-/- T cells. The Il17 promoter is BATF-responsive, and after TH17 differentiation, BATF binds conserved intergenic elements in the Il17a–Il17f locus and to the Il17, Il21 and Il22 (ref. 18) promoters. These results demonstrate that the AP-1 protein BATF has a critical role in TH17 differentiation.

The transcription factor BATF controls the global regulators of class-switch recombination in both B cells and T cells.

Abstract: The transcription factor BATF controls the differentiation of interleukin 17 (IL-17)-producing helper T cells (T(H)17 cells) by regulating expression of the transcription factor RORγt itself and RORγt target genes such as Il17. Here we report the mechanism by which BATF controls in vivo class-switch recombination (CSR). In T cells, BATF directly controlled expression of the transcription factors Bcl-6 and c-Maf, both of which are needed for development of follicular helper T cells (T(FH) cells). Restoring T(FH) cell activity to Batf(-/-) T cells in vivo required coexpression of Bcl-6 and c-Maf. In B cells, BATF directly controlled the expression of both activation-induced cytidine deaminase (AID) and of germline transcripts of the intervening heavy-chain region and constant heavy-chain region (I(H)-C(H)). Thus, BATF functions at multiple hierarchical levels in two cell types to globally regulate switched antibody responses in vivo.

T cell exhaustion

Abstract: T cell exhaustion is a state of T cell dysfunction that arises during many chronic infections and cancer. It is defined by poor effector function, sustained expression of inhibitory receptors and a transcriptional state distinct from that of functional effector or memory T cells. Exhaustion prevents optimal control of infection and tumors. Recently, a clearer picture of the functional and phenotypic profile of exhausted T cells has emerged and T cell exhaustion has been defined in many experimental and clinical settings. Although the pathways involved remain to be fully defined, advances in the molecular delineation of T cell exhaustion are clarifying the underlying causes of this state of differentiation and also suggest promising therapeutic opportunities.

Differentiation of Effector CD4 T Cell Populations

Abstract: CD4 T cells play critical roles in mediating adaptive immunity to a variety of pathogens. They are also involved in autoimmunity, asthma, and allergic responses as well as in tumor immunity. During TCR activation in a particular cytokine milieu, naive CD4 T cells may differentiate into one of several lineages of T helper (Th) cells, including Th1, Th2, Th17, and iTreg, as defined by their pattern of cytokine production and function. In this review, we summarize the discovery, functions, and relationships among Th cells; the cytokine and signaling requirements for their development; the networks of transcription factors involved in their differentiation; the epigenetic regulation of their key cytokines and transcription factors; and human diseases involving defective CD4 T cell differentiation.

Innate and adaptive immune cells in the tumor microenvironment

Abstract: Most tumor cells express antigens that can mediate recognition by host CD8(+) T cells. Cancers that are detected clinically must have evaded antitumor immune responses to grow progressively. Recent work has suggested two broad categories of tumor escape based on cellular and molecular characteristics of the tumor microenvironment. One major subset shows a T cell-inflamed phenotype consisting of infiltrating T cells, a broad chemokine profile and a type I interferon signature indicative of innate immune activation. These tumors appear to resist immune attack through the dominant inhibitory effects of immune system-suppressive pathways. The other major phenotype lacks this T cell-inflamed phenotype and appears to resist immune attack through immune system exclusion or ignorance. These two major phenotypes of tumor microenvironment may require distinct immunotherapeutic interventions for maximal therapeutic effect.

Understanding the tumor immune microenvironment (TIME) for effective therapy.

Abstract: The clinical successes in immunotherapy have been both astounding and at the same time unsatisfactory. Countless patients with varied tumor types have seen pronounced clinical response with immunotherapeutic intervention; however, many more patients have experienced minimal or no clinical benefit when provided the same treatment. As technology has advanced, so has the understanding of the complexity and diversity of the immune context of the tumor microenvironment and its influence on response to therapy. It has been possible to identify different subclasses of immune environment that have an influence on tumor initiation and response and therapy; by parsing the unique classes and subclasses of tumor immune microenvironment (TIME) that exist within a patient's tumor, the ability to predict and guide immunotherapeutic responsiveness will improve, and new therapeutic targets will be revealed.

Development of Monocytes, Macrophages, and Dendritic Cells

Abstract: Monocytes and macrophages are critical effectors and regulators of inflammation and the innate immune response, the immediate arm of the immune system. Dendritic cells initiate and regulate the highly pathogen-specific adaptive immune responses and are central to the development of immunologic memory and tolerance. Recent in vivo experimental approaches in the mouse have unveiled new aspects of the developmental and lineage relationships among these cell populations. Despite this, the origin and differentiation cues for many tissue macrophages, monocytes, and dendritic cell subsets in mice, and the corresponding cell populations in humans, remain to be elucidated.