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

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 ADAPdeficient, 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 pathological 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 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.

Lymphocyte proliferation in immune-mediated diseases

“…In addition, RIP-GP mice receiving Smarta CD4 T cells, which exhibit increased homeostatic proliferation and autoimmune diabetes upon cyclophosphamide treatment, actually have greater numbers of FoxP3 + Treg cells than do controls; this may be due to the higher proportions of Treg cells and memory cells that are present during lymphopenia [22,32]. Furthermore, Treg cell numbers are not altered in ADAP-deficient mice that show a greater incidence of diabetes and homeostatic proliferation compared to control mice [33]. However, Treg cells in these models might not function as effectively, resulting in increased homeostatic proliferation and disease despite similar or higher Treg numbers compared to controls [64].…”

“…ADAP regulates positive selection and a deficiency in ADAP leads to decreased thymic output, thus promoting the observed homeostatic expansion. Importantly, transfer of either leukocytes or purified T cells into ADAP-deficient mice led to decreased diabetes incidence and reduced homeostatic proliferation [33]. Furthermore, it has been reported that rheumatoid arthritis patients show decreased thymic output that might lead to increased T cell proliferation in the periphery with an increased autoreactive T cell pool [34].…”

T Cell–Independent Modulation of Experimental Autoimmune Encephalomyelitis in ADAP-Deficient Mice

“…In transplantation models, ADAP-deficient mice showed prolonged heart graft survival and ameliorated rejection of intestinal allografts (17,18). In contrast, ADAP-deficient TCR-transgenic mice revealed an increased incidence of autoimmune diabetes (19). In platelets, loss of ADAP results in impaired a IIb b 3 integrin activation, leading to increased rebleeding of ADAPdeficient mice from tail wounds (20) and to instable thrombus formation after carotid artery injury in vivo (21).…”

Short Communication FYB polymorphisms in Brazilian patients with type I diabetes mellitus and autoimmune polyglandular syndrome type III

“…The study performed by Zou et al (2008) highlighted some important results indicating that the FYB protein displays a key action in modulating T cells behavior in non-obese diabetic (NOD) mice. In addition, their results indicated that FYB is present in the pathogenic events in T1DM in murine models.…”

“…This protein is involved in T cell signaling activation, and participates in integrin-mediated adhesion, cytoskeletal actin reorganization, and in the stability and duration of cell-cell contact (Griffiths et al, 2001;Wang and Rudd, 2008;Pauker et al, 2011). Since Zou et al (2008) observed that the loss of FYB leads to defective thymocyte selection and a striking enhancement of T1DM incidence in FYB knockout mice, it could be speculated that this protein might participate in disease establishment. Single nucleotide polymorphisms (SNPs) within the FYB gene (5p13.1) might alter the concentration or function of the protein and, as consequence, contribute to T1DM development.…”