# Modulating costimulation pathways to improve follicular helper T cell and antibody responses

> **NIH VA I01** · VA NEW JERSEY HEALTH CARE SYSTEM · 2022 · —

## Abstract

T follicular helper (TFH) cells are essential for establishing protective immunity in responses to infection
and immunization, where they help high-affinity antibody production by germinal center (GC) B cells,
generation of plasma cells and memory B cells. The TFH-B cell cooperativity thus constitutes the cornerstone of
immunological memory formation induced by vaccines. Deciphering pathways and factors that promote TFH cell
differentiation and function is a prerequisite for formulating more efficacious vaccines.
 In response to infection or immunization, activated CD4+ T cells undergo stage-wise differentiation to
become functionally competent TFH cells. These stages include early stage TFH lineage specification to
generate nascent TFH cells, GC response stage to mature to GC-TFH cells, and later stage formation of memory
TFH cells. Vaccines are delivered as live-attenuated viruses, inactivated organisms, or protein subcomponents
via different routes. It has not drawn enough attention whether all TFH cells are created equal by different
vaccination approaches.
 We extended our in vivo studies to CD28 and ICOS costimulatory receptors, which are well-established
TFH regulators. CD28-PYAP and ICOS-YMFM intracellular motifs are preferentially connected to PKCq/PDK1
and PI3K-Akt pathways, respectively. Current views hold that CD28 is critical for initiating and ICOS for
sustaining TFH responses. Contrary to this belief, our preliminary data revealed that the ICOS-YMFM motif is
essential for initiating Imm_TFH, while the CD28-PYAP motif was indispensable for sustaining Inf_TFH
responses. These findings led to our central hypothesis that TFH cells have distinct molecular
requirements depending on activating agents/approaches, where CD28 and ICOS motifs differentially
regulate Inf_TFH and Imm_TFH cells in a stage-specific manner. To test this, we designed multi-layered
functional and molecular studies in 3 specific aims:
Specific Aim 1. To define differential requirements for CD28 and ICOS motifs in TFH fate specification.
Specific Aim 2. To delineate CD28 and ICOS motif-controlled molecular circuits that promote GC-TFH
 cell maturation and B-cell help function.
Specific Aim 3. To investigate the roles of CD28 and ICOS motifs in memory TFH persistence and recall
response.
 Developing efficacious vaccines against infectious diseases is thus essential for protecting troops in
service as well as veterans. Our proposed study directly addresses this need, by advancing the understanding
of TFH cells at new frontiers. We expect to yield essential information on tailoring TFH activity to provide optimal
B cell help, and hence provide paradigm-shifting rationales for enhancing vaccine design.

## Key facts

- **NIH application ID:** 10367461
- **Project number:** 1I01BX005771-01
- **Recipient organization:** VA NEW JERSEY HEALTH CARE SYSTEM
- **Principal Investigator:** Hai-Hui Xue
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2022-01-01 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10367461

## Citation

> US National Institutes of Health, RePORTER application 10367461, Modulating costimulation pathways to improve follicular helper T cell and antibody responses (1I01BX005771-01). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10367461. Licensed CC0.

---

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