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B7-CD28 co-stimulation modulates central tolerance via thymic clonal deletion and Treg generation through distinct

Masashi Watanabe1, Ying Lu1, Michael Breen1

  • 1Experimental Immunology Branch, National Cancer Institute, Bethesda, MD, 20892, USA.

Nature Communications
|December 9, 2020
PubMed

Insights

B7-CD28 co-stimulation is crucial for preventing autoimmunity by eliminating self-reactive T cells (thymic central tolerance) and generating regulatory T cells (Treg). This process shapes the T cell repertoire to avoid autoimmune diseases.

Area of Science:

  • Immunology
  • Molecular Biology
  • Cellular Biology

Background:

  • Mechanisms of thymic central tolerance and autoimmunity prevention are not fully understood.
  • The role of B7-CD28 co-stimulation in T cell development requires further elucidation.

Purpose of the Study:

  • To investigate the role of B7-CD28 co-stimulation in thymic central tolerance.
  • To determine the involvement of specific antigen-presenting cell (APC) types in these processes.
  • To understand how B7-CD28 signaling impacts regulatory T (Treg) cell generation and clonal deletion.

Main Methods:

  • Studied B7-CD28 co-stimulation and B7 expression on APCs.
  • Investigated clonal deletion and Treg cell generation from tissue-restricted antigen (TRA)-specific thymocytes.
  • Differentiated CD28 signaling requirements and APC dependencies for tolerance induction.

Main Results:

  • B7-CD28 co-stimulation and B7 expression by specific APCs are essential for clonal deletion and Treg cell generation.
  • Clonal deletion and Treg induction have distinct CD28 signaling requirements and APC dependencies (dendritic cells, B cells, thymic epithelial cells).
  • Defective B7-CD28 signaling impairs thymic deletion, leading to peripheral accumulation of self-reactive T cells and autoimmunity.

Conclusions:

  • B7-CD28 co-stimulation is vital for shaping the T cell repertoire.
  • Thymic central tolerance is maintained through both clonal deletion and Treg cell generation, regulated by B7-CD28 interactions.
  • Dysregulation of B7-CD28 signaling contributes to the development of autoimmune diseases.

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