Fig. 1: Immunofluoresence staining for viperin (green) with CD45RB220 (red) in spleens of wild-type (left) and knockout (right) mice.
Reproduced from Ref. 1 © 2009 The American Society of Hematology
A team of researchers led by Biomedical Sciences Institutes investigator Keh-Chuang Chin and including colleagues in Singapore and the USA have obtained new insights into how the protein viperin helps to mobilize one division of the immune system against foreign threats by observing T-cell development in its absence.
The credentials of viperin as a contributor to the human antiviral response process are well established, and production of this protein is boosted in response to infection by a variety of pathogens. Until recently, however, little was known about its specific involvement in driving immune system activity.
Viperin is primarily expressed in the spleen, a nexus for peripheral T-cell production, and Chin’s group began by examining changes in helper T-cell activity in mice in which the viperin gene had been knocked out (Fig. 1). Helper T cells normally differentiate into two major categories of ‘effector’ cells: Th1 cells, which stimulate antigen-consuming macrophages, and Th2 cells, which activate antibody-producing B cells. Although overall helper T-cell levels were unaffected in viperin-deficient mice, these animals exhibited apparent deficiencies in Th2 activity, as evidenced by impaired immune response to foreign antigens and reduced levels of Th2-specific immunostimulatory chemical signals.
Th2 maturation occurs through two parallel pathways, one driven by signaling molecules known as cytokines and the other triggered via activation of the T-cell receptor (TCR). Chin and colleagues found that although the former pathway functions normally without viperin, the latter appears to depend in part on this protein. Closer analysis of helper T cells from knockout animals revealed the reason: a marked reduction in levels of GATA-3, the ‘master regulator’ protein responsible for Th2 differentiation in response to TCR activation. Notably, these defects were most apparent in T cells examined three days after TCR activation, suggesting that viperin acts at a relatively late stage in TCR-mediated Th2 differentiation. This was further supported by findings that early responses to TCR activity, such as cell proliferation and calcium flux, were unaffected by the absence of viperin.
Subsequent experiments suggested that viperin is required for the proper formation of the NF-κB and AP-1 multi-protein complexes, which are known drivers of GATA-3 gene activity but which also regulate numerous other genes related to inflammatory and immune response pathways—leaving many unresolved questions. “We have provided evidence here for a crucial role of viperin in helper T cell development and differentiation,” concludes Chin, “but its precise physiological function in the immune system has not been fully elucidated.”
The A*STAR-affiliated authors on this highlight are from the Singapore Immunology Network (SIgN).
