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Protein kinase C-theta is required for efficient positive selection.

Sharon Celeste Morley1, K Scott Weber, Henry Kao

  • 1Department of Pediatrics, Division of Pediatric Infectious Diseases, Washington University School of Medicine, St. Louis, MO 63110, USA.

Journal of Immunology (Baltimore, Md. : 1950)
|September 20, 2008
PubMed
Summary

Protein kinase C-theta (PKCtheta) is crucial for T cell receptor (TCR) signaling in mature T cells. Re-evaluation shows PKCtheta is also vital for thymocyte development and positive selection, impacting T cell generation.

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Area of Science:

  • Immunology
  • Cell Biology
  • Molecular Biology

Background:

  • Protein kinase C-theta (PKCtheta) is essential for T cell receptor (TCR)-mediated signaling in mature T cells.
  • Previous studies indicated no role for PKCtheta in thymocyte development, despite overlapping signaling pathways with mature T cells.

Purpose of the Study:

  • To re-evaluate the role of PKCtheta in thymocyte development and positive selection.
  • To investigate the impact of PKCtheta deficiency on TCR signaling during T cell maturation.

Main Methods:

  • Utilized the n3.L2 TCR-transgenic mouse model to study PKCtheta's function.
  • Analyzed thymocyte development and positive selection in PKCtheta knockout mice using flow cytometry and bone marrow chimeras.
  • Assessed TCR signaling strength and ERK activation in thymocytes.

Main Results:

  • PKCtheta deficiency resulted in impaired thymocyte positive selection, reducing CD4 single-positive thymocyte and mature T cell generation by 50%.
  • Bone marrow chimera experiments showed a >80% reduction in CD4+ thymocytes from PKCtheta(-/-) progenitors, indicating a cell-intrinsic defect.
  • Weaker TCR signaling and diminished ERK activation were observed in PKCtheta-deficient thymocytes, contributing to inefficient positive selection.
  • Similar defects in positive selection of both CD4 and CD8 single-positive thymocytes were observed in non-transgenic PKCtheta(-/-) mice.

Conclusions:

  • PKCtheta plays a critical role in thymocyte positive selection, a process essential for T cell development.
  • These findings establish PKCtheta as a key signaling molecule in both thymocyte positive selection and mature T cell activation.
  • Compensatory mechanisms by other PKC isoforms may explain incomplete selection defects in PKCtheta-deficient thymocytes.