# The cell and molecular mechanisms underlying CD28 costimulation

> **NIH NIH R37** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2023 · $403,750

## Abstract

CD28 is a T cell surface molecule that can provide a second signal, when combined with immobilized TCR
ligands, to induce naïve T activation. Costimulation results from the interaction of CD28 with its ligands CD80
(B7.1) and CD86 (B7.2) induced on activated antigen-presenting cells by activation of the innate immune
system. We do not have a good molecular understanding of how CD28 mediates its costimulatory signals.
Models and experimental evidence have suggested that CD28 either: 1) augments the magnitude of TCR
signaling; or, 2) provides a unique signal, qualitatively distinct from that provided by the TCR. It is important to
understand the molecular signaling pathways underlying costimulation since interrupting costimulation has
been important clinically. A deeper insight into CD28 signaling pathways may enable the development of new
therapeutics that would be useful in blocking the immune system. Very recent studies from my lab provide
some new insights and suggest approaches and clues that will enable us identify previously unrecognized
components of the CD28-regulated signaling pathways and permit a more complete understanding of CD28
signaling. These chemical-biology, genetic and proteomic studies lead us to hypothesize that an important
consequence of CD28 costimulation is the regulation of the actin cytoskeleton and this influences
signals downstream of the TCR. We will explore this via the following specific aims: 1) Determine the
mechanism by which costimulation modulates the actin cytoskeleton to facilitate PLCγ1 mediated hydrolysis of
PIP2 in double positive (CD4+CD8+, DP) thymocytes and in more mature T cells; 2) Determine how CD28
overcomes a negative regulatory influence of Pyk2 and Cbl-b on T cell signaling leading to IL-2 production and
T cell proliferation; and, 3) Using recently obtained phosphoproteomic data, we will identify key components of
the pathway downstream of CD28 and those that modulate the actin cytoskeleton in response to CD28
costimulation.

## Key facts

- **NIH application ID:** 10534131
- **Project number:** 5R37AI114575-08
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** ARTHUR WEISS
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $403,750
- **Award type:** 5
- **Project period:** 2015-12-01 → 2025-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10534131

## Citation

> US National Institutes of Health, RePORTER application 10534131, The cell and molecular mechanisms underlying CD28 costimulation (5R37AI114575-08). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10534131. Licensed CC0.

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