# Regulation of lupus pathogenesis through modulation of thymic development of pathobiont-specific T cells

> **NIH NIH R00** · UNIVERSITY OF VIRGINIA · 2024 · $248,999

## Abstract

PROJECT SUMMARY/ABSTRACT
CANDIDATE: I am a postdoctoral research associate in the laboratory of Dr. Gretchen E. Diehl in the
Immunology Program at Memorial Sloan-Kettering Cancer Center. I obtained my PhD working in gut
microbiota and systemic lupus erythematosus under the supervision of Dr. Martin Kriegel. My current research
applies the techniques I learned in my postdoc and graduate school to assess the role of gut microbes in the
thymic development of microbiota-specific T cells and how these T cells can modulate disease in susceptible
hosts. To elucidate this process, I used a tetramer-based approach to identify and track antigen-specific T cells
expansion in the thymus before they distribute and differentiate in the periphery. I plan to study how this
process is altered in autoimmunity. My proposed research and mentoring plan will provide me the required
foundation to transition into an independent researcher with a long-term career goal to understand how
microbiota-specific T cell responses arise and define how they exacerbate lupus pathogenesis. To achieve this
goal, together with my mentoring team, I have developed a career plan that will 1) increase my technical skills,
2) refine my scientific scope, 3) improve my communication skills, and 4) expand my scientific network.
RESEARCH: Lupus development is associated with intestinal dysbiosis in patients and mouse models.
Dysbiosis in lupus is characterized by pathobiont overgrowth and is linked to dysregulated immune responses
that exacerbate pathogenesis. In my graduate work, I found increased pathobionts including Lactobacillus
reuteri in mouse lupus models and subsets of SLE patients. I showed L. reuteri translocated systemically,
leading to increased inflammatory pathways and proinflammatory T cells which exacerbated systemic
inflammation and worsened lupus pathogenesis. In my postdoctoral work, I am investigating how differentiation
of microbiota-specific T cells is regulated during development and its effects in inflammatory processes. While
we and others find peripheral expansion of microbiota-specific T cells with effector function in adult mice, in
young mice we surprisingly found microbiota-specific T cells first expanded in the thymus, a site not previously
known to allow for antigen-specific T cell expansion. I aim to synergize the knowledge generated during my
graduate and postdoctoral training to determine if thymic development of L. reuteri-specific T cells is amplified
in lupus susceptible hosts and to assess their role in lupus exacerbation. I will develop this proposal by 1)
Determining how thymic microbiota-specific T cells modulate lupus pathogenesis and 2) Defining how lupus
pathobionts modulate pathobiont-specific T cells expansion.
ENVIRONMENT: The laboratory is part of the Immunology program at Memorial Sloan-Kettering Cancer
Center, a state-of-the-art research institute. Furthermore, my mentoring committee and collaborators will
provide the required scientific and ...

## Key facts

- **NIH application ID:** 10974052
- **Project number:** 4R00AR080207-03
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Daniel Fernando Zegarra Ruiz
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $248,999
- **Award type:** 4N
- **Project period:** 2023-12-01 → 2026-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10974052

## Citation

> US National Institutes of Health, RePORTER application 10974052, Regulation of lupus pathogenesis through modulation of thymic development of pathobiont-specific T cells (4R00AR080207-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10974052. Licensed CC0.

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