Transcriptional network dynamics in early T cell development.

The rate at which cells enter the T cell pathway depends not only on the immigration of hematopoietic precursors into the strong Notch signaling environment of the thymus but also on the kinetics with which each individual precursor cell reaches T-lineage commitment once it arrives. Notch triggers a complex, multistep gene regulatory network in the cells in which the steps are stereotyped but the transition speeds between steps are variable. Progenitor-associated transcription factors delay T-lineage differentiation even while Notch-induced transcription factors within the same cells push differentiation forward.

Integrative genomic analysis identifies unique immune environments associated with immunotherapy response in diffuse large B cell lymphoma.

Most diffuse large B-cell lymphoma (DLBCL) patients treated with bispecific antibodies (BsAb) or chimeric antigen receptor (CAR) T cells fail to achieve durable treatment responses, underscoring the need for a deeper understanding of mechanisms that regulate the immune environment and response to treatment. Here, an integrative, multi-omic approach was employed to characterize DLBCL immune environments, which effectively segregated DLBCLs into four quadrants - termed DLBCL-immune quadrants (IQ) - defined by cell-of-origin and immune-related gene set expression scores. Recurrent genomic alterations were enriched in each IQ, suggesting that lymphoma cell-intrinsic alterations contribute to orchestrating unique DLBCL immune environments.

MHC cross-dressing in antigen presentation.

Dendritic cells (DCs) orchestrate T cell responses by presenting antigenic peptides on major histocompatibility complex (MHC) and providing costimulation and other instructive signals. Professional antigen presenting cells (APCs), including DCs, are uniquely capable of generating and presenting peptide antigens derived from exogenous proteins. In addition to these canonical cross-presentation and MHC-II presentation pathways, APCs can also display exogenous peptide/MHC (p/MHC) acquired from neighboring cells and extracellular vesicles (EVs).

Speed and navigation control of thymocyte development by the fetal T-cell gene regulatory network.

T-cell differentiation is a tightly regulated developmental program governed by interactions between transcription factors (TFs) and chromatin landscapes and affected by signals received from the thymic stroma. This process is marked by a series of checkpoints: T-lineage commitment, T-cell receptor (TCR)β selection, and positive and negative selection. Dynamically changing combinations of TFs drive differentiation along the T-lineage trajectory, through mechanisms that have been most extensively dissected in adult mouse T-lineage cells.

Dendritic cells can prime anti-tumor CD8 T cell responses through major histocompatibility complex cross-dressing.

Antigen cross-presentation, wherein dendritic cells (DCs) present exogenous antigen on major histocompatibility class I (MHC-I) molecules, is considered the primary mechanism by which DCs initiate tumor-specific CD8 T cell responses. Here, we demonstrate that MHC-I cross-dressing, an antigen presentation pathway in which DCs acquire and display intact tumor-derived peptide:MHC-I molecules, is also important in orchestrating anti-tumor immunity. Cancer cell MHC-I expression was required for optimal CD8 T cell activation in two subcutaneous tumor models.

Divergent fates of antigen-specific CD8 T cell clones in mice with acute leukemia.

The existence of a dysfunctional CD8 T cell state in cancer is well established. However, the degree to which CD8 T cell fates are influenced by the context in which they encounter cognate tumor antigen is less clear. We previously demonstrated that CD8 T cells reactive to a model leukemia antigen were deleted by antigen cross-presenting type 1 conventional dendritic cells (cDC1s).

gene alterations identify a subset of diffuse large B-cell lymphoma harboring a T-cell-inflamed phenotype.

Programmed death-ligand 1 (PD-L1) expression on malignant cells is a dominant immune escape mechanism across a variety of human cancers. A unique genetic mechanism underlying PD-L1 upregulation has been uncovered in classical Hodgkin lymphoma (cHL), in which copy gains of the chromosomal region (9p24.1) containing the programmed death-1 (PD-1) ligands and are recurrently observed.

Negligible Role for Deletion Mediated by cDC1 in CD8 T Cell Tolerance.

Deletion of CD8 T cells by dendritic cells (DCs) is recognized as a critical mechanism of immune tolerance to self-antigens. Although DC-mediated peripheral deletion of autoreactive CD8 T cells has been demonstrated using T cells reactive to model Ags, its role in shaping the naturally occurring polyclonal CD8 T cell repertoire has not been defined. Using mice lacking cross-presenting CD8α and CD103 DCs (also known as type 1 conventional [cDC1]), we demonstrate that peripheral deletion of CD8 T cells reactive to a model tissue Ag is dependent on cDC1.

CD8α Dendritic Cells Dictate Leukemia-Specific CD8 T Cell Fates.

APCs are essential for the orchestration of antitumor T cell responses. Batf3-lineage CD8α and CD103 dendritic cells (DCs), in particular, are required for the spontaneous initiation of CD8 T cell priming against solid tumors. In contrast, little is known about the APCs that regulate CD8 T cell responses against hematological malignancies.