Defective positive selection results in T cell lymphopenia and increased autoimmune diabetes in ADAP-deficient BDC2.5-C57BL/6 mice.
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.
Zou
Liangxing
L
Department of Internal Medicine and Center for Immunology, University of Minnesota, Minneapolis, MN 55455, USA.
Mendez
Felipe
F
Martin-Orozco
Natalia
N
Peterson
Erik J
EJ
D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D006706:Homeostasis / Q000276:immunology; D018655:Lymphocyte Count; D008231:Lymphopenia / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; C491468:Fyb protein, mouse