# Studying cognate interactions of follicular Tregs and germinal center B cells

> **NIH NIH R21** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $195,000

## Abstract

Project Summary
Cellular and molecular mechanisms that control self-specificity and the magnitude of humoral (antibody, Ab)
responses are still poorly understood. To evoke high-affinity Ab response, B cells have to acquire foreign
antigen and receive help from cognate T helper (Th) cells. This leads to generation of short-lived plasma cells
and Germinal Center (GC) B cells. Within GCs, B cells mutate their B cell receptors (BCRs), receive help from
follicular helper T cells (Tfh), undergo affinity maturation, and differentiate into memory B cells and long-lived
plasma cells that enable long-term humoral immunity. However, random mutation of BCRs in GC B cells can
also lead to generation of self-reactive GC B cells and thus enable development of plasma cells that produce
self-reactive Abs and promote autoimmunity. Multiple studies indicate an important role of follicular regulatory
T cells (Tfr) in the control of self-specificity and magnitude of Germinal Center responses. However, whether
Tfrs that recognize self antigen-acquiring and presenting GC B cells in a cognate fashion can directly act on
these GC B cells to promote their apoptosis or modify B cell interactions with Tfh cells in vivo is unknown. The
objective of this application is to determine whether Tfr cells exert significant negative regulation of cognate
self-reactive GC B cells in vivo and address the mechanism of this control by intravital two-photon imaging of
GC B cell, Tfr cells, and Tfh cell interactions in murine lymph nodes (LNs). Our central hypothesis is that direct
interactions between cognate Tfr cells and GC B cells promotes elimination of self antigen-presenting GC B
cell clones. This hypothesis is based on the previously published work suggesting that Tfr deficiency results
into accumulation of bystander GC B cells and generation of anti-nuclear antibodies and autoimmunity. We will
test our central hypothesis by combining standard immunological approaches with novel intravital imaging of
cognate and non-cognate interactions between GC B cells, Tfr cells, and Tfh cells in the LNs of living mice.
The expected out-come of the proposed work is to better understand the mechanisms that control self-
specificity of humoral responses in vivo. Such results are expected to have an important positive impact
because they could lead to development of novel strategies for control and treatment of self-reactive Ab-
mediated autoimmunity and for better manipulation of humoral responses against pathogens.

## Key facts

- **NIH application ID:** 9849739
- **Project number:** 5R21AI142032-02
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Irina Leonidovna Grigorova
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $195,000
- **Award type:** 5
- **Project period:** 2019-01-11 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9849739

## Citation

> US National Institutes of Health, RePORTER application 9849739, Studying cognate interactions of follicular Tregs and germinal center B cells (5R21AI142032-02). Retrieved via AI Analytics 2026-08-10 from https://api.ai-analytics.org/grant/nih/9849739. Licensed CC0.

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