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

• Published in: European journal of immunology Vol. 38; no. 4; pp. 986 - 994
• Main Authors: Zou, Liangxing, Mendez, Felipe, Martin-Orozco, Natalia, Peterson, Erik J.
• Format: Journal Article
• Language: English
• Published: 01-04-2008
• ISSN: 0014-2980; 1521-4141
• DOI: 10.1002/eji.200737881

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-A
g7
, and in mice carrying one I-A
b
allele (BDC/B6
g7/b
). Increased disease correlates with significantly reduced numbers of pathologic CD4
+
T cells in the mice. Consistent with a state of functional lymphopenia in ADAP-deficient BDC/B6
g7/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 (SP) thymocyte compartment in ADAP-deficient BDC/B6
g7/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/B6
g7/b
model. Our findings support the notion that ineffective thymic T cell output can be a powerful causative factor in lymphopenia-driven autoimmune diabetes.