Defective positive selection results in T cell lymphopenia and increased autommune diabetes in ADAP-deficient BDC2.5-C57BL/6 mice

Liangxing Zou, Felipe Mendez, Natalia Martin-Orozco, Erik J. Peterson

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

Adhesion and degranulation promoting adapter protein (ADAP), a positive regulator of T cell receptor (TCR) signaling, is required for thymocyte development and T cell homeostasis. To investigate the role of ADAP in a T cell-driven autoimmune response, we generated ADAP-deficient, BDC2.5 TCR transgenic, diabetes-prone (C57BL/6) mice (BDC/B6). We observed a striking enhancement of diabetes incidence in ADAP-deficient mice, both in animals homozygous for I-Ag7, and in mice carrying one I-Ab allele (BDC/B6g7/b). Increased disease correlates with significantly reduced numbers of pathological CD4+ T cells in the mice. Consistent with a state of functional lymphopenia in ADAP-deficient BDC/B6g7/b mice, T cells display increased homeostatic proliferation. Transfer of syngeneic lymphocytes or T cells both blocks ADAP-dependent diabetes and relieves exaggerated homeostatic T cell proliferation observed in ADAP-deficient mice. Marked attenuation in cellularity of the CD4+ single-positive thymocyte compartment in ADAP-deficient BDC/B6g7/b animals suggests a mechanism for induction of the lymphopenia. We conclude that inefficient positive selection in ADAP deficiency results in lymphopenia that leads to enhanced autoimmune diabetes in the BDC/B6g7/b model. Our findings support the notion that ineffective thymic T cell output can be a powerful causative factor in lymphopenia-driven autoimmune diabetes.

Original languageEnglish (US)
Pages (from-to)986-994
Number of pages9
JournalEuropean Journal of Immunology
Volume38
Issue number4
DOIs
StatePublished - Apr 2008

Keywords

  • Adhesion and degranulation-promoting adapter protein
  • Autoimmune diabetes
  • BDC2.5
  • Lymphopenia
  • Thymocyte development

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