# NIH grant: Fate-Mapping and Genetic Dissection of B-to-T Feedback Circuits Shaping Germinal-Center Selection (1R21AI202288-01) — retained record

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[original source ↗](https://reporter.nih.gov/project-details/1R21AI202288-01)

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NIH grant 1R21AI202288-01: Fate-Mapping and Genetic Dissection of B-to-T Feedback Circuits Shaping Germinal-Center Selection
Institute: {'code': 'AI', 'abbreviation': 'NIAID', 'name': 'National Institute of Allergy and Infectious Diseases', 'admin_org_id': '12500003', 'admin_funding_url': ''}. PI: David  Dominguez-Sola. Award: $210000.
Start: 2026-08-07T00:00:00.
Project Summary/Abstract
Protective antibody responses depend on tightly coordinated interactions between B and T cells within germinal
centers (GCs). These transient encounters determine the fate of B cells and are essential to support antibody
affinity maturation and long-term immunity. Although T cell help is well recognized as essential for GC function,
how B cells reciprocally signal back to T cells—and how this feedback influences GC dynamics and antibody
quality—remains poorly understood.
Our preliminary work revealed that a small subset of positively selected, MYC⁺ GC B cells transiently express
CD70, a ligand of the TNF superfamily that binds CD27 on T cells. Germline CD70 or CD27 loss-of-function
mutations in humans cause combined immunodeficiency, EBV-driven lymphoproliferation, and autoimmunity,
whereas somatic loss-of-function CD70 mutations recur in aggressive B-cell lymphomas. Conversely, CD70
overexpression in tumors promotes immune evasion. These opposing disease outcomes suggest that
CD70/CD27 signaling is critical for immune balance.
The goal of this R21 project is to uncover how transient CD70 expression in GC B cells shapes antibody
responses and the fates of both B and T follicular helper (Tfh) cells. We integrate new in vivo genetic systems
that, for the first time, allow direct visualization and fate mapping of transient B–T interactions mediated by
CD70/CD27.
Aim 1 will determine the function of CD70 and its associated signaling module during antibody responses and
GC dynamics and, using a new strategy for quick genetic modification of GC in vivo, determine how loss or
restoration of Cd70 in GC B cells affects GC responses. Aim 2 will map the cellular interactions and fate
decisions driven by CD70/CD27 signaling. We will generate two complementary models: (1) a CD70–CD27
LIPSTIC system (Labeling Immune Partnerships by SorTagging Intercellular Contacts) that enzymatically labels
B and T cells engaging in these interactions in vivo, and (2) a Cd70 fate-mapping allele that permanently labels
B cells transiently expressing CD70 during selection. Using single-cell transcriptomics and lineage tracking, we
will define the transcriptional programs and fates of both interacting partners.
This work is innovative in combining newly engineered genetic models, synthetic cis-regulatory reporters, and
targeted gene delivery platforms to resolve the transient, reciprocal signaling events that govern adaptive
immunity. The expected outcome is a mechanistic framework explaining how B-to-T feedback through
CD70/CD27 maintains GC homeostasis and prevents immune dysregulation.
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