Biology subjects

Mujal, A. M.

Publications and source records attributed to Mujal, A. M..

3 recordsLinked to original sources

bioRxiv2023

Early antigen receptor signaling in natural killer cells alters STAT4-dependent fate decisions via epigenetic remodeling

Lymphocyte differentiation depends on activation via antigen and cytokines during the immune response to infection. How the timing and integration of these signals program the epigenetic and functional fate of these cells is not completely understood. In this study, we find that interleukin (IL)-12 signaling received by innate and adaptive lymphocytes has a context-dependent role for immune memory formation. In the absence of a preceding and/or sufficient antigen receptor signaling event, IL-12 impairs the adaptive expansion of cytotoxic lymphocytes. In contrast, sufficient antigen-receptor signaling redirects inflammatory cytokine signals to promote memory differentiation via cooperation of STAT4 and AP-1 transcription factors. By this crucial epigenetic mechanism, optimally equipped lymphocytes are selected for memory formation rather than a terminal effector cell fate. Whereas T cells are hardwired to be shielded from premature IL-12 signaling, NK cells rely on coincidental early antigen receptor signaling for adaptive responses. Together, step-wise integration of antigen and cytokine signaling optimizes both effector and memory differentiation, allowing for promiscuous recruitment into the acute immune response while promoting avidity maturation in memory populations of both innate and adaptive lymphocytes. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/565992v2_ufig1.gif" ALT="Figure 1"> View larger version (64K): org.highwire.dtl.DTLVardef@192b969org.highwire.dtl.DTLVardef@1cabd1aorg.highwire.dtl.DTLVardef@145139aorg.highwire.dtl.DTLVardef@9faae_HPS_FORMAT_FIGEXP M_FIG C_FIG Key points- Adaptive NK cell responses rely on sequential integration of antigen and inflammatory signals. - Epigenetic redirection of STAT4 genomic binding promotes adaptive programming. - CD8+ T cell fate depends on antigen-dependent integration of inflammatory signaling. - STAT/AP-1 cooperation underlies step-wise integration of antigen and cytokine signaling in NK cells and CD8+ T cells.

immunology↗

bioRxiv2021

Holistic Characterization of Tumor Monocyte-to-Macrophage Differentiation Integrates Distinct Immune Phenotypes in Kidney Cancer

The tumor immune microenvironment (TIME) is commonly infiltrated by diverse collections of myeloid cells. Yet, the complexity of myeloid cell identity and plasticity has challenged efforts to define bona fide populations and determine their connections to T cell function and their relation to patient outcome. Here we leverage single-cell RNA-sequencing (scRNA-seq) analysis of several mouse and human tumors and find that monocyte-macrophage diversity is characterized by a combination of conserved lineage states as well as transcriptional programs accessed along the differentiation trajectory. Using mouse models, we also find that tumor monocyte-to-macrophage progression is profoundly tied to regulatory T cell (Treg) abundance. Importantly, in human kidney cancer, heterogeneity in macrophage accumulation and myeloid composition corresponded to variance in, not only Treg density, but also the quality of infiltrating CD8+ T cells. In this way, holistic analysis of monocyte-to-macrophage differentiation creates a framework for critically different immune states in kidney tumors.

immunology↗

bioRxiv2019

Tumors Exploit Dedicated Intracellular Vesicles to Program T cell Responses

In order to drive productive tumor-infiltrating lymphocyte (TIL) function, myeloid populations must direct antigens to the lymph node, including to resident antigen-presenting cells (APCs) that have never touched the tumor. It has long been supposed that APCs trade antigens with one another, but the dominant cell biology underlying that remains unknown. We used in vitro and in vivo assays together with lattice light sheet and multiphoton imaging to show that myeloid cells carry tumor antigen-laden vesicles that they trade with one another as they reach distant sites. This accounts for the majority of antigen displayed to T cells and provides tumors with a mechanism to access APCs that differentially direct T cell activation away from memory phenotypes. This work defines efficient cell biology that drives the first steps of TIL generation and represents a new frontier for engineering tumoral immunity.

immunology↗