V o l . 2 1 N o . 6 2 5 3

J U N E 2 0 0 0

U P D A T EI M M U N O L O G Y TO D AY

Current literature

Direct manipulation of T-cell responses isthe goal of many therapies for immunologi-cal disorders. Stimulation of the B7–CD28costimulatory pathway is associated with anincreased anti-tumour immune response,whereas blocking this pathway inhibits theprogression of a potentially fatal complica-tion of bone-marrow transplantation – graft-versus-host disease (GVHD; in which allo-geneic lymphocytes react against host tissuein an immunocompromised recipient).

Tamada et al. have identified a T-cell co-stimulatory pathway involving a recentlydescribed member of the tumour necrosisfactor family, LIGHT. LIGHT [whose namederives from: homologous to lymphotoxins,shows inducible expression, and competeswith herpes simplex virus glycoprotein Dfor herpes virus entry mediator (HVEM), areceptor expressed by T lymphocytes] bindswith high affinity to the T-cell receptorHVEM and to the lymphotoxin b receptor(LTbR) found on monocytes and stromalcells. Blocking HVEM is known to inhibit allogeneic mixed lymphocyte reactions.

The group show that LIGHT stimulatesmouse T-cell proliferation in the presence,but not the absence, of immobilized anti-CD3

antibody – demonstrating the requirementof an antigenic signal. Furthermore, LIGHTcostimulates CD282 T cells to the same degree as CD281 T cells, indicating a CD28-independent pathway.

The isolation of a mouse LIGHT homo-logue enabled investigation of these costim-ulatory effects in vivo. Tumour regression wasobserved in mice injected with LIGHT cDNA,an effect reversed by depletion of CD81 T cells,indicating the costimulation of cytotoxic Tlymphocyte (CTL) anti-tumour responses.

Conversely, the treatment of GVHD aimsto reduce CTL responses. By infusing a soluble form of the LIGHT receptor lym-photoxin b receptor (LTbR-Ig), Tanaka et al.prevented the onset of GVHD in immuno-compromised recipient mice – suggestingthat blocking the LIGHT costimulatorypathway prevents disease progression.

Questions remain over the relevance ofother possible functions of LIGHT, and of alternative receptors. Nevertheless, investi-gation of this previously unknown costim-ulatory pathway could provide novel therapeutic targets for the treatment oftransplantation and cancer.Bea Perks

Stress-related immunosuppressionand opioid-dependent Fas expressionYin, D. et al. (2000) Chronic restraint stresspromotes lymphocyte apoptosis by modulatingCD95 expression. J. Exp. Med. 191, 1423–1428

Enhanced susceptibility to infection has longbeen linked to psychological or physicalstress. It is accepted that stressors induce therelease of hormones and neurotransmitters;now, Yin et al. describe a direct mechanismby which stress affects immune responses.Using a model in which mice were subjectedto chronic physical restraint over 48 hours,they show that the number of splenocytes instressed animals is significantly reduced.Not only is this process directly related to anincrease in CD95 (Fas/APO-1) expression,but it seems to be dependent on the activityof endogenous opioids.

When subject to physical restraint for two12-hour periods over two days, BALB/cmice developed severe reduction in spleniclymphocyte numbers: a decrease of 30–45%compared with unstressed controls. The lossof lymphocytes was correlated with increasedapoptosis, as demonstrated by the terminaldeoxynucleotidyl transferase-mediated de-oxyuridine triphosphate nick end labeling(TUNEL) assay. In parallel, it was shownthat expression of CD95, but not CD95-ligand(CD95L) was increased in splenocytes fromstressed animals, and that blocking CD95–CD95L interactions diminished cell loss. Thestress-induced changes in CD95 expressionand lymphocyte number could also beblocked by the opioid receptor antagonistsnaltrexone or naloxone. Strikingly, the re-duction of splenocytes in this model systemseems to be independent of the hypo-thalamo-pituitary-adrenal (HPA) axis, asboth adrenalectomized and sham-operatedmice exhibited similar responses to chronicstress.

This paper makes an important contribu-tion to our understanding of the neuroim-munology of stress, demonstrating that thestress-dependent release of endogenous opi-oids can directly and rapidly suppress theimmune system through CD95-mediatedapoptosis. The next step will be to identifythe specific opioid receptor types involved,and their detailed role in connecting neuraland immunological systems.

Rob Brines

T-cell costimulation in a new LIGHTTamada, K. et al. (2000) Modulation of T-cell-mediated immunity in tumour and graft-versus-host disease models through the LIGHT costimulatory pathway. Nat. Med. 6, 283–289

Tumour necrosis factor (TNF) family mem-bers are important regulators of immunefunction and play a role in lymph nodeorganogenesis, inflammatory responses andlymphocyte activation. Abnormal levels ordecreased expression of TNF and relatedmolecules are known to contribute to in-flammatory disorders and autoimmune dis-eases. zTNF4 (also known as BAFF, BLyS,TALL-1 and THANK) is a recent addition tothe TNF family.

In the present study, Gross et al. describethe overexpression of zTNF4 in lymphoidcells of transgenic mice. The mice developan autoimmune disease that resembles systemic lupus erythematosus. They exhibit elevated levels of serum IgG and IgM andhave increased numbers of activated B cellsin enlarged lymph nodes and spleen. zTNF4transgenic mice also have elevated numbersof splenic B-1a cells, a population of cells

that are known to predominantly produceself-reactive IgM antibodies. Gross et al. alsoshow that circulating zTNF4 is more abun-dant in NZBWF1 and MRL-lpr/lpr mice, whichare used as models for lupus-like diseases.

Gross et al. have now identified two TNF-Rhomologues, TACI and BCMA, that bind tozTNF4 and are expressed predominantly onB cells and activated T cells. A zTNF4 decoyreceptor was generated by fusing the extra-cellular portion of TACI to the constant region ‘tail’ of IgG. Treatment of NZBWF1mice with the TACI-Ig fusion protein delayedproteinuria, decreased the number of pe-ripheral B cells and suppressed the develop-ment of lupus-like disease in these animals.

Following recent success using TNF decoyreceptors to treat rheumatoid arthritis, zTNF4now joins the growing ranks of potential targets for therapy of autoimmune diseases.Elaine Bell

TNF-R homologues in autoimmune diseaseGross, J.A. et al. (2000) TACI and BCMA are receptors for a TNF homologue implicated in B-cell autoimmune disease. Nature 404, 995–999