Editors' ChoiceImmunology

When a Better Immune Response Is Bad

Science Signaling  25 Aug 2009:
Vol. 2, Issue 85, pp. ec280
DOI: 10.1126/scisignal.285ec280

Women infected with human immunodeficiency virus 1 (HIV-1) are at increased risk of developing acquired immunodeficiency syndrome (AIDS) compared to men with the same viral load. Meier et al. analyzed the response of plasmacytoid dendritic cells (pDCs) from gender-matched patients to HIV-1–derived ligands or inactivated HIV-1 that stimulates Toll-like receptors (TLRs) 7 and 8 and found that although the same percentage of cells responded between men and women, cells from women exhibited a greater production of interferon-α (IFN-α) but not tumor necrosis factor–α (TNF-α). In contrast, there was no gender-based difference in the response to ligands of TLR9. The concentration of plasma progesterone correlated with the percentage of pDCs that produced IFN-α in response to an HIV-1–derived TLR7 and TLR8 ligand, and postmenopausal women showed a lower percentage of IFN-α–producing pDCs than did premenopausal women when challenged with the TLR7/8 ligand. IFN-α stimulates CD8-positive T cells (cytotoxic T cells) to produce CD38, a surface glycoprotein the abundance of which is a predictor of HIV-1 disease progression. T cells from women showed a greater increase in CD38 abundance after stimulation with HIV-1–derived TLR7/8 ligands or inactivated virus than did T cells from men. After adjusting for HIV-1 viral load, chronically HIV-infected women had a greater percentage of CD8- and CD38-positive T cells compared with T cells from HIV-infected men. Thus, the increased TLR7 and TLR8 responsiveness of women, which may be modulated by circulating steroid hormones, leads to greater IFN-α secretion and accumulation of cytotoxic T cells and disease progression.

A. Meier, J. J. Chang, E. S. Chan, R. B. Pollard, H. K. Sidhu, S. Kulkarni, T. F. Wen, R. J. Lindsay, L. Orellana, D. Mildvan, S. Bazner, H. Streeck, G. Alter, J. D. Lifson, M. Carrington, R. J. Bosch, G. K. Robbins, M. Altfeld, Sex differences in the Toll-like receptor–mediated response of plasmacytoid dendritic cells to HIV-1. Nat. Med. 15, 955–959 (2009). [PubMed]