CD28 is a T cell surface molecule that can provide a second signal, when combined with immobilized TCR ligands, to induce nave 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 PLC?1 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.

Public Health Relevance

T lymphocytes, an important cellular component of protective and pathologic immune responses, require two signals to be activated. One, mediated by the T cell antigen receptor, ensures only specific responses occur, and the second, mediated by CD28, ensures that the T cell is responding to pathogens that have triggered awareness by the immune system. New results from different experimental approaches provide us with clues to gain a molecular understanding of how CD28 stimulates T cells which could lead to the design of better therapeutics to boost or control T cell responses.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Method to Extend Research in Time (MERIT) Award (R37)
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Cellular and Molecular Immunology - A Study Section (CMIA)
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Mallia, Conrad M
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University of California San Francisco
Internal Medicine/Medicine
Schools of Medicine
San Francisco
United States
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Shang, Wanjing; Jiang, Yong; Boettcher, Michael et al. (2018) Genome-wide CRISPR screen identifies FAM49B as a key regulator of actin dynamics and T cell activation. Proc Natl Acad Sci U S A 115:E4051-E4060
Smith, Geoffrey A; Taunton, Jack; Weiss, Arthur (2017) IL-2R? abundance differentially tunes IL-2 signaling dynamics in CD4+ and CD8+ T cells. Sci Signal 10:
Esensten, Jonathan H; Helou, Ynes A; Chopra, Gaurav et al. (2016) CD28 Costimulation: From Mechanism to Therapy. Immunity 44:973-88