# Dissecting the role of HVEM and BTLA in constraining the germinal center B cell response

> **NIH NIH F30** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2020 · $50,520

## Abstract

Project summary/abstract
Germinal centers (GC) are regions in lymphoid organs where activated B cells are selected for their ability to
bind antigen with high affinity as well as generate memory B cells and high affinity antibodies. GC B cells have
the unique ability to improve their affinity to the immunizing antigen during an immune response through a
process of somatic hypermutation and selection. Although somatic hypermutation targets the immunoglobulin
genes, off-target mutations also occur and contribute to the malignant transformation of GC B cells into a subset
of non-Hodgkin B cell lymphomas. Our understanding of GC B cell biology has been greatly enriched by
understanding how such mutations over-ride the normal constraints to GC B cell growth. For instance, our lab
has shown S1PR2’s role in confining GC B cells to the GC and inhibiting growth by antagonizing Akt signaling.
HVEM, a TNF receptor superfamily member (also called TNFRSF14), is frequently mutated in germinal center
(GC) derived non-Hodgkin B cell lymphomas such as follicular lymphoma and diffuse large B cell lymphoma.
The mutations found in HVEM are predicted to lead to loss of the protein’s function, suggesting an important
growth regulatory role for HVEM in GC B cells. However, HVEM’s function in B cells has not been directly
examined. HVEM is highly expressed on follicular B cells and is expressed at a lower level on GC B cells,
possibly suggesting an advantage to more finely tuned signaling in the GC. In preliminary studies we have found
that deficiency in HVEM results in a cell intrinsic expansion of GC B cells. Of HVEM’s binding partners, the
immunoglobulin (Ig) superfamily co-inhibitory receptor B and T lymphocyte attenuator (BTLA) is most highly
expressed in the GC. BTLA is highly expressed on T follicular helper (Tfh) cells and BTLA deficiency in antigen-
specific CD4+ T cells increases IL-21 production and GC B cell expansion, suggesting a regulatory role of BTLA
on Tfh cells. Tfh cells have a crucial role in GC B cell selection and several molecular regulators have been
shown to tune the degree of T cell help provided to the GC B cell. We hypothesize that HVEM acts as a
suppressor of GC B cell responses through its interaction with BTLA, a potential negative regulator of B and T
cell engagement. Specifically, we aim to assess how HVEM regulates the magnitude of the GC B cell response
and if it impacts the induction of long-lived humoral immunity (1); and to examine if BTLA expression on T
follicular helper cells moderates the amount of T cell help during the GC reaction (2). This work will define a
novel negative regulator of the GC B cell response, which can lead to a rational target for vaccine development,
immunotherapy, and treatment for GC-derived B cell lymphomas.

## Key facts

- **NIH application ID:** 9836794
- **Project number:** 5F30AI131496-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Michelle Mintz
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $50,520
- **Award type:** 5
- **Project period:** 2017-01-01 → 2020-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9836794

## Citation

> US National Institutes of Health, RePORTER application 9836794, Dissecting the role of HVEM and BTLA in constraining the germinal center B cell response (5F30AI131496-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9836794. Licensed CC0.

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