Mark R. Alderson

Fas and FasL in the homeostatic regulation of immune responses

Studies of the biological effects of Fas signaling, using transformed cell lines as targets, indicate that ligation of the Fas receptor induces an apoptotic death signal. Chronically activated normal human T cells are also susceptible to Fas-mediated apoptosis. However, interactions between Fas and Fas ligand can also yield a costimulatory signal. Here, David Lynch, Fred Ramsdell and Mark Alderson present a model for the role of As and FasL in the homeostatic regulation of normal immune responses. They discuss how dysregulation of the Fas apoptotic pathway may contribute to certain disease states, including autoimmune disease and human immunodeficiency virus (HIV)-induced depletion of CD4+ T cells.

The mouse fas-ligand gene is mutated in gld mice and is part of a TNF family gene cluster

The gene for the mouse Fas ligand was cloned and its chromosomal position determined. Fasl was tightly linked to gld (no crossovers in 567 meiotic events) on mouse chromosome 1 and closely linked with a novel member of the same TNF family of ligands, the Ox40 ligand (Ox40l, 1 crossover in 567 meiotic events). Southern blot analysis did not reveal any difference between the Fasl gene from gld and wild-type mice and levels of Fasl mRNA transcripts were similar in PMA and ionomycin induced wild-type and coisogenic gld T cells. Sequence analysis of the gld gene indicated a single amino acid change (Phe Leu) in the COOH terminal portion of this type II transmembrane protein, and COS cells transfected with Fasl cDNA from gld mice failed to induce apoptosis of Fas-expressing target cells. Thus, the data demonstrate that the gld phenotype is the result of a point mutation in the Fasl gene and that Fasl is part of a complex of ligands structurally related to TNF mapping within a small region of mouse chromosome 1.

Activation of HIV expression by CD30 triggering in CD4+ T cells from HIV-infected individuals

CD30 is a member of the tumor necrosis factor receptor superfamily, preferentially expressed by T cells producing type 2 helper (Th2) cytokines, whose ligand (CD30L) has been identified on B cells, activated macrophages, and a subset of activated T cells. We show here that cross-linking CD30 with an agonistic CD30-specific monoclonal antibody, as well as with CD30L+ CD8+ T cell clones or CD30L+ B cells, enhanced HIV replication in CD4+ T cells from HIV-infected individuals, and such a potentiating effect was inhibited by anti-CD30L antibody. The anti-CD30L antibody also exerted a suppressive effect on spontaneous HIV replication occurring in lymph node cells from an HIV-sero-positive patient, showing CD30L expression by both B and CD8+ T lymphocytes. Thus, CD30 triggering by CD30L-expressing cells may plan an important role in the activation of HIV expression from latently infected CD4+ T cells.