# Chemokines and Lymphoid Tissue Organization and Function

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2022 · $469,994

## Abstract

Project Summary/Abstract
 B cell selection in germinal centers (GCs) is important for the success of antibody responses against
influenza, HIV-1 and many other pathogens. However, the full set of signals involved in mounting GC
responses is not understood. Recent work highlights the importance of signals from T follicular helper (Tfh)
cells in driving preferential outgrowth of higher affinity B cells. The factors determining the strength and quality
of signaling between Tfh cells and B cells are incompletely defined and are a focus of this proposal.
 The surface receptor HVEM (TNFRSF14) is frequently mutated in human GC-derived lymphomas
(follicular lymphoma and GCB-diffuse large B cell lymphoma). This finding suggests HVEM has an important
role in normal GC function but this role has not been defined. We have found that HVEM deficiency gives B
cells a competitive advantage over wild-type B cells during GC responses. Our preliminary data suggest that
this advantage only occurs when T cells are capable of sensing HVEM through expression of BTLA. We
therefore propose a model where HVEM engagement of BTLA on Tfh cells restrains the amount of T cell help
delivered to the B cell. The first Aim will define how HVEM restrains the competitiveness of B cells for
representation in the GC. Adoptive transfer and conditional deletion approaches will be used to determine the
stage(s) of the B cell response at which HVEM acts. The function of the HVEM intracellular domain will be
tested using retroviral gene transduction approaches and the effects of HVEM deficiency on plasma cell
formation, affinity maturation and recall responses will be determined.
 The second Aim will define how BTLA within CD4 T cells determines the quality of help received by the
B cell. We will use retroviral gene transduction to test the role of the BTLA cytoplasmic domain in Tfh cell
function. Analysis of T cells lacking the tyrosine phosphatases, SHP1 and SHP2, will define their roles in BTLA
function. The influence of HVEM-BTLA engagement on cell-cell contact and T cell signaling will be studied
using intravital 2-photon microscopy combined with the Salsa6f calcium reporter. Erk signaling will be followed
using a new nuclear-cytoplasmic translocation reporter mouse line.
 The final Aim will examine how loss of the HVEM-BTLA interaction contributes to GC-derived
lymphomagenesis. We will test whether BTLA functions as an extrinsic tumor suppressor by testing for
accelerated outgrowth of Bcl2-overexpressing GC B cells in mice lacking BTLA in T cells. We will test for
possible co-oncogenic effects of combined HVEM- and Gna13-deficiency.
 By defining how HVEM and BTLA act to control T cell help of B cell responses, this work may point to
new approaches for augmenting B cell diversification and affinity maturation in GCs. An understanding of how
HVEM constrains GC B cell accumulation, including cells over-expressing Bcl2, will provide insights that may
lead to new approaches for treatment ...

## Key facts

- **NIH application ID:** 10471837
- **Project number:** 5R01AI045073-24
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Jason G Cyster
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $469,994
- **Award type:** 5
- **Project period:** 1999-04-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10471837

## Citation

> US National Institutes of Health, RePORTER application 10471837, Chemokines and Lymphoid Tissue Organization and Function (5R01AI045073-24). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10471837. Licensed CC0.

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