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Updated: Aug 8, 2026
Isolation and Th17 Differentiation of Naïve CD4 T Lymphocytes
Published on: September 27, 2013
Distinct regions in the CD28 cytoplasmic domain are required for T helper type 2 differentiation
Pietro G Andres1, Kimberly C Howland, Ajay Nirula
1Division of Gastroenterology, Department of Medicine, University of California, San Francisco, California 94143, USA.
Insights
CD28 costimulation impacts T cell responses differently. While proliferation and IL-2 production need general CD28 signaling, IL-4 production and T helper type 2 differentiation depend on specific CD28 tail motifs and 3-phosphoinositide-dependent protein kinase 1.
Area of Science:
- Immunology
- Molecular Biology
- Cell Biology
Background:
- CD28 costimulation is critical for CD4(+) T cell functions, including proliferation, survival, IL-2 production, and T helper type 2 (Th2) development.
- Understanding the specific signaling pathways downstream of CD28 is essential for deciphering T cell responses.
Purpose of the Study:
- To investigate the structure-function relationship of the CD28 cytoplasmic tail in mediating distinct T cell functional outcomes.
- To identify the molecular mechanisms underlying CD28-driven T cell proliferation, IL-2 production, and IL-4 production.
Main Methods:
- Structure-function analysis of the CD28 cytoplasmic tail in primary T cells.
- Gene-complementation assays to assess the role of specific signaling molecules.
Main Results:
- CD28-mediated T cell proliferation and IL-2 production were independent of specific cytoplasmic domains.
- IL-4 production and Th2 differentiation were driven by the cooperative action of specific motifs within the CD28 cytoplasmic tail.
- 3-phosphoinositide-dependent protein kinase 1 was identified as a key mediator of the Th2 differentiation signal downstream of CD28.
Conclusions:
- Distinct signaling mechanisms govern different CD28-mediated T cell functional responses.
- Specific motifs in the CD28 cytoplasmic tail, along with downstream kinases like PDK1, are crucial for Th2 cell differentiation.
Abstract:
CD28 costimulation is essential for CD4(+) T cell proliferation, survival, interleukin 2 (IL-2) production and T helper type 2 development. To define the nature of the signals that may drive different T cell responses, we have done a structure-function analysis of the CD28 cytoplasmic tail in primary T cells. CD28-mediated T cell proliferation and IL-2 production did not require a particular cytoplasmic domain. In contrast, IL-4 production was driven by the cooperative activity of specific motifs within the CD28 cytoplasmic tail. Using a gene-complementation approach, we provide evidence that one component of this T helper type 2 differentiation signal was mediated by 3-phosphoinositide-dependent protein kinase 1. Thus, different mechanisms underlie the induction of distinct T cell functional responses by CD28.
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