Identification of astrocyte-derived immune suppressor factor that induces apoptosis of autoreactive T cells.

In experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis, apoptosis of T cells is mainly seen at inflammation sites of the central nervous system (CNS). Cumulative data suggests that astrocytes might render T cells susceptible to induction of apoptotic cell death. We observed that apoptotic cell death of proteolipid protein (PLP)-reactive T cells was induced by an interferon (IFN)-γ-treated astrocyte cell line. In this study, we have identified and cloned the genes derived from the IFN-γ-treated astrocyte cell line that induce apoptosis of autoreactive T cells. We created subtraction cDNA libraries from the IFN-γ-treated astrocyte cell line and obtained 100 positive clones. After screening of subtracted cDNAs, we found two candidate genes that induced apoptosis of the PLP-reactive T cell line. The first is a previously unknown gene of 726 base pairs that we named astrocyte-derived immune suppressor factor (AdIF). It contained an open reading frame encoding a polypeptide of 228 amino acids. The second was SPARC/osteonectin, a multifunctional glycoprotein secreted in the extracellular matrix. AdIF protein was found at the inflammatory sites of the EAE brain, and bound to the surface of CD4(+) T cells. Purified recombinant AdIF protein inhibited the proliferation of activated PLP-reactive CD4(+) T cells and induced their apoptosis in vitro. Intravenous administration of recombinant AdIF protein to mice with in which acute EAE was induced prevented the incidence of EAE and suppressed the symptoms. The newly discovered molecule AdIF may render auto-reactive T cells susceptible to the induction of apoptotic cell death and could potentially be a new therapeutic agent for multiple sclerosis.