Molecular checkpoints in myeloid and B cell responses
Abstract/Contents
- Abstract
- After physical barriers, the innate immune response is the first line of defense against pathogens. The adaptive immune confers long-lasting pathogen-specific immune memory poised to be rapidly recruited upon secondary infection. Innate responses rest on the ability of immune cells to recognize pathogens associated molecular patterns (PAMPs) via pattern recognition receptors (PRRs) thus triggering activation of an inflammatory response that together with adaptive immunity aids pathogen clearance. PRRs are also expressed by adaptive immune cells. PRR signaling in adaptive immune cells can promote their activation and skew maturation. Although the role of PRRs in sensing PAMPs is well established, it is becoming increasingly clear that the immune system can also by activated by certain endogenous ("self") molecules. Immune cell activation also often includes substantial metabolic reprogramming. In this thesis we investigate the role of two pathways necessary for optimal immune responses: self-dsRNA/ADAR1 and sterol/SREBP. Cytosolic double stranded RNA (dsRNA) is recognized as a viral PAMP. However, dsRNA can also be generated as a byproduct of the transcription of repetitive genomic elements. Under normal homeostatic conditions, the enzyme adenosine deaminase acting on RNA-1 (ADAR1), modifies self-dsRNA to prevent sensing by PRRs. Despite evidence that ADAR1 is a central negative regulator of self-dsRNA sensing, our understanding of the contribution of the self-dsRNA/ADAR1 axis to the initiation, propagation, and durability of the immune response is limited. Here, we demonstrate a role for ADAR1 in CD11c+ myeloid antigen presenting cells (APCs) and germinal center (GC) B cells. We show that ADAR1 loss in APCs skews the composition of the myeloid cellular compartment and imprints a functional antiviral transcriptional signature in the lungs. Meanwhile, ADAR1 loss in GC B cells leads to a failure to generate successful humoral and memory B cell responses to immunization. These results reveal a fundamental role for ADAR1 in regulating the innate and adaptive immune response. Sterol regulatory element binding proteins (SREBPs) are transcription factors that promote the expression of genes involved in cholesterol uptake. The SREBP cleavage activating protein (SCAP) mediates SREBP activation. Our previous work identified an association between the magnitude of the antibody response in humans and targets of SREBP. To understand whether this effect was mediated by APCs or was B cell intrinsic, we generated mouse models of conditional SCPAP deletion in both CD11c+ myeloid APCs and B cell. We demonstrated that SREBP signaling in B cells (but not APCs) was essential for effective B cell response. SCAP deficiency led to cell cycle progression and maturation defects. Taken together, our findings provide new mechanistic insights about the regulation of immune responses by the RNA-editing enzyme ADAR1 and by SREBP/SCAP mediated cholesterol biosynthesis.
Description
| Type of resource | text |
|---|---|
| Form | electronic resource; remote; computer; online resource |
| Extent | 1 online resource. |
| Place | California |
| Place | [Stanford, California] |
| Publisher | [Stanford University] |
| Copyright date | 2023; ©2023 |
| Publication date | 2023; 2023 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Author | Adamska, Julia Zofia |
|---|---|
| Degree supervisor | Li, Jin (Billy) |
| Degree supervisor | Pulendran, B. (Bali) |
| Thesis advisor | Li, Jin (Billy) |
| Thesis advisor | Pulendran, B. (Bali) |
| Thesis advisor | Engleman, Edgar G |
| Thesis advisor | Kirkegaard, Karla |
| Thesis advisor | Mellins, Elizabeth |
| Degree committee member | Engleman, Edgar G |
| Degree committee member | Kirkegaard, Karla |
| Degree committee member | Mellins, Elizabeth |
| Associated with | Stanford University, School of Medicine |
| Associated with | Stanford University, Department of Microbiology and Immunology |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Julia Zofia Adamska. |
|---|---|
| Note | Submitted to the Department of Microbiology and Immunology. |
| Thesis | Thesis Ph.D. Stanford University 2023. |
| Location | https://purl.stanford.edu/sw846vv6396 |
Access conditions
- Copyright
- © 2023 by Julia Zofia Adamska
- License
- This work is licensed under a Creative Commons Attribution 3.0 Unported license (CC BY).
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