Aberrant T-lymphocyte development and function in mice overexpressing human soluble amyloid precursor protein-α: implications for autism

1. Antoinette R. Bailey*,
2. Huayan Hou*,
3. Demian F. Obregon*,
4. Jun Tian*,
5. Yuyan Zhu*,
6. Qiang Zou*,
7. William V. Nikolic‡,
8. Michael Bengtson*,
9. Takashi Mori§,
10. Tanya Murphy† and
11. Jun Tan*,²

+ Author Affiliations

1. ^*Rashid Laboratory for Developmental Neurobiology, Silver Child Development Center, Department of Psychiatry and Neurosciences, and
2. ^†Rothman Center for Neuropsychiatry, Department of Pediatrics, All Children's Hospital, College of Medicine, University of South Florida, Tampa, Florida, USA;
3. ^‡Department of Genetics, Faculty of Medicine, University of Kragujevac, Svetozara, Kragujevac, Serbia; and
4. ^§Departments of Biomedical Sciences and Pathology, Saitama Medical Center and Saitama Medical University, Kawagoe, Saitama, Japan

1. ↵2Correspondence: Rashid Laboratory for Developmental Neurobiology, Silver Child Development Center, Department of Psychiatry and Neurosciences, College of Medicine, University of South Florida, 3515 E. Fletcher Ave. Tampa, FL 33613, USA. E-mail: jtan@hsc.usf.edu

Abstract

Abnormalities in T-lymphocyte populations and function are observed in autism. Soluble amyloid precursor protein α (sAPP-α) is elevated in some patients with autism and is known to be produced by immune cells. In light of the well-established role of sAPP-α in proliferation, growth, and survival of neurons, we hypothesized an analogous role in the immune system. Thus, we explored whether sAPP-α could modulate immune development and function, especially aspects of the pinnacle cell of the adaptive arm of the immune system: the T cell. To do this, we generated mice overexpressing human sAPP-α and characterized elements of T-cell development, signal transduction, cytokine production, and innate/adaptive immune functions. Here, we report that transgenic sAPP-α-overexpressing (TgsAPP-α) mice displayed increased proportions of CD8⁺ T cells, while effector memory T cells were decreased in the thymus. Overall apoptotic signal transduction was decreased in the thymus, an effect that correlated with dramatic elevations in Notch1 activation; while active-caspase-3/total-caspase-3 and Bax/Bcl-2 ratios were decreased. Greater levels of IFN-γ, IL-2, and IL-4 were observed after ex vivo challenge of TgsAPP-α mouse splenocytes with T-cell mitogen. Finally, after immunization, splenocytes from TgsAPP-α mice displayed decreased levels IFN-γ, IL-2, and IL-4, as well as suppressed ZAP70 activation, after recall antigen stimulation. Given elevated levels of circulating sAPP-α in some patients with autism, sAPP-α could potentially drive aspects of immune dysfunction observed in these patients, including dysregulated T-cell apoptosis, aberrant PI3K/AKT signaling, cytokine alterations, and impaired T-cell recall stimulation.—Bailey, A. R., Hou, H., Obregon, D. F., Tian, J., Zhu, Y., Zou, Q., Nikolic, W. V., Bengtson, M., Mori, T., Murphy, T., Tan, J. Aberrant T-lymphocyte development and function in mice overexpressing human soluble amyloid precursor protein-α: implications for autism.

• T cells
• sAPP-α
• transgenic mice

• Received August 31, 2011.
• Accepted November 1, 2011

Aberrant T-lymphocyte development and function in mice overexpressing human soluble amyloid precursor protein-α: implications for autism