# Signaling and Selection in Germinal Center B Cells

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $457,682

## Abstract

The germinal center (GC) response is central in generating long-lived humoral immunity and the basis for
effective vaccination. GC B cells (GCBC) extensively remodel their transcription factor (TF) networks and gene
expression. GCBC undergo V region somatic hypermutation that generates the substrate for a cyclic process of
positive and negative selection in which surviving GCBC divide 3-4 times per day. Among the most pivotal
questions in GC biology is how signals lead to positive selection of higher affinity B cells, either by entering a
new cycle of cell division and/or rescue from cell death. How is selection in GC balanced against death and
differentiation into one of two possible long-lived fates: memory B cell (MBC) and long-lived plasma cell (LLPC).
Recent studies have identified certain putative surface markers as well as opposing and interacting transcription
factor networks that may control these events. One important clue comes from our recent studies showing that
the early GC reaction tends to spawn MBC while the late phase largely generates LLPC. In this proposal we will
use novel approaches to ask how different signals and downstream pathways interact to determine GCBC fate
(selection and MBC/PC differentiation and to elucidate precursor-product relationships of GCBC and progeny.
In work supported by our first cycle of funding, we have been focusing on how Ag-dependent signals—either
directly, via BCR, or indirectly, via recruitment of T cell help through antigen presentation—control the fate of
GCBC during positive selection in the GC. We found that BCR and CD40 signaling are dramatically
reprogrammed in GCBC compared to naïve B cells (NBC), with signaling from both receptors being substantially
yet selectively attenuated. In contrast to NBC, GCBC require both BCR and CD40 to ignite a positive selection
signal, as read out by expression of c-MYC and generation of p-S6. These observations raise a number of
outstanding questions. First, are IL-21 signals also interpreted differently by GCBC, as we found that IL21 and
CD40 stimulation only synergistically induce c-MYC in GCBC? Second, are cytokine signals contributing to
positive selection and determining how GCBC differentiate and if so, how? Mechanistically, since we know that
signals act in concert and synergistically, we would like to understand how BCR, CD40 and cytokine signals
interact, or “crosstalk”. Elucidating mechanisms of signal reprogramming and crosstalk will reveal how signals to
GCBC are integrated at the molecular level to determine appropriate responses of those cells. We will test a
hypothetical model that posits that early in the reaction, Ag is abundant and BCR signals predominate, which
favors MBC generation and GC maintenance, while at later stages IL-21 signals prevail, which favors plasma
cell generation. To test this model we will investigate, in Aim 1, how IL-21R signals are rewired in GCBC; in Aim
2, how, mechanistically, BCR/CD40 and IL-21/CD40 signals di...

## Key facts

- **NIH application ID:** 9981071
- **Project number:** 2R01AI105018-06
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** MARK J SHLOMCHIK
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $457,682
- **Award type:** 2
- **Project period:** 2014-03-15 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9981071

## Citation

> US National Institutes of Health, RePORTER application 9981071, Signaling and Selection in Germinal Center B Cells (2R01AI105018-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9981071. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*