# Role of thymic B cells in immune tolerance

> **NIH NIH K99** · UNIVERSITY OF MINNESOTA · 2024 · $138,051

## Abstract

Project Summary/Abstract
Generation of a functional adaptive immune response relies on the collaboration of the cellular (T cell) and
humoral (B cell) compartments. T follicular helper (Tfh) cells provide essential help to B cells to undergo
isotype class-switch recombination and generate high-affinity antibody through somatic hypermutation.
Follicular regulatory T (Tfr) cells have been implicated in controlling this process as they have been shown to
be critical in regulating germinal center B cell responses and prevent autoantibody formation. However, how
these Tfr cells develop is unknown. B cells undergo a unique type-III interferon dependent and isotype class-
switching process in the thymus, the location of T cell development, and induce clonal deletion and Treg cell
selection. Developing Treg cells that depend on licensed thymic B cell antigens may also interact with
activated B cells in the periphery and take on a Tfr phenotype. Thus, Treg cells selected by thymic B cells may
become Tfr cells in the periphery and help to reduce the risk autoantibody generation.
The objective of this work is to understand what role licensed thymic B cells play in T cell tolerance. In this
proposal we identified T cell receptors that generate Tfr cells when expressed by developing T cells, propose
to study the requirements of these TCRS for selection as well as explore further functional consequences
when thymic B cells are absent. Our central hypothesis is that type-III interferon drives thymic B cell
licensing, resulting in the presentation of B cell activation induced self-peptides, thereby supporting
the development of Treg cells that become Tfr cells and regulate humoral immune responses.
Through this work we hope to generate a mechanistic understanding of the impact of thymic B cell activation
on immune tolerance. These findings will have the potential to reveal new pathways regulating adaptive
immune responses and have implications in our understanding of autoimmune diseases like systemic lupus
erythematous or rheumatoid arthritis, diseases where pathogenic autoreactive antibodies mediate disease. I
am applying for this K99/R00 as an Instructor in Laboratory Medicine and Pathology Department with
subspecialty training in Molecular Pathology. My long-term career goals are to support for the clinical diagnosis
of autoimmunity and inborn errors of immunity and to lead an R01 funded research program that investigates
central tolerance and immunodeficiency.

## Key facts

- **NIH application ID:** 10947644
- **Project number:** 1K99AI184587-01
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** Ryan J Martinez
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $138,051
- **Award type:** 1
- **Project period:** 2024-07-12 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10947644

## Citation

> US National Institutes of Health, RePORTER application 10947644, Role of thymic B cells in immune tolerance (1K99AI184587-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10947644. Licensed CC0.

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