The role of Sp110 in human T cell apoptosis and immunopathology

SP110 deficiency in humans causes veno-occlusive disease with immunodeficiency (VODI, OMIM: 235550), a rare and often fatal primary immunodeficiency. Clinically, patients present with hepatic veno-occlusive disease and typically life-threatening pneumocystis infections, although T- and B-cell numbers are normal. Pneumocystis pneumonia is known to be aggravated by T cell mediated immunopathology. Sp110 is a family member of the Sp100/Sp140 protein family which associates with PML- nuclear bodies. Sp110 is known to be upregulated by interferons (IFN) and is believed to modulate gene transcription. However, how SP110 affects immunity and T cell function in particular is very poorly understood.
In my PhD thesis we characterized a previously unknown role of Sp110 as a key T cell intrinsic immune-regulatory protein. First, we demonstrated that high T cell intrinsic Sp110 protein levels augment re-stimulation induced T cell apoptosis. This Sp110 dependent c-Jun/JNK signaling pathway dependent apoptosis was associated with increased caspase 9 activity, while extrinsic, FAS mediated apoptosis was much less affected by Sp110. We also demonstrated that type I interferon treatment (IFN I) of primary human T cell blasts augmented Sp110 levels such that augmented Sp110 dependent T cell apoptosis was observed.
Second, we demonstrated that Sp110 deficiency augmented re-stimulation induced c-Jun/JNK dependent T cell intrinsic interferon-γ production. Application of these findings in VODI patients suggest that Sp110 deficient T cells fail to undergo re-stimulation induced apoptosis while secreting non-regulated amounts of interferon-γ. This likely explains the particular susceptibility of VODI patients to pneumocystis pneumonia but also identifies Sp110 as an essential immune regulatory protein in diseases associated with augmented IFN-I formation such as chronic virus infections, systemic autoimmune diseases or some primary (monogenic) immunodeficiencies.