© 2005 Nature Publishing Group

100 | FEBRUARY 2005 | VOLUME 5 www.nature.com/reviews/immunol

with the TReg

-cell-associated transcription factorFOXP3 (forkhead box P3) can be used to inducea regulatory phenotype. Foxp3-transducedpolyclonal CD4+ T cells from non-obese dia-betic (NOD) mice produced the regulatorycytokine interleukin-10 after stimulationwith CD3-specific antibody and suppressed

the proliferation of naive CD4+CD25–

responder cells in co-culture. However,these Foxp3-transduced poly-

clonal T cells had no effecton disease when trans-

ferred to NOD mice withrecent-onset diabetes. A

therapeutic effect wasonly obtained when

the T cells to betransduced withFoxp3 were iso-

lated from T-cellreceptor (TCR)-trans-

genic mice that recog-nize a pancreatic-islet

antigen. Such T cells showed specific

homing to, and activation in, the pancreaticdraining lymph nodes, indicating that theantigen specificity of the T

Regcells will be

important in determining therapeutic efficacy.One potential method for redirecting the

antigen specificity of polyclonal TReg

cells isdescribed by Mekala and Geiger. They trans-genically modified the T

Regcells with a chimeric

receptor consisting of a myelin basic protein(MBP) epitope bound to the extracellular andtransmembrane domains of MHC linked tothe cytoplasmic domain of the TCR ζ-chain.Such receptor-modified T cells specificallyrecognize, and are activated by, T cells specificfor the MBP epitope. Receptor-modified CD4+

CD25+ T cells inhibited both the onset anddevelopment of EAE induced with MBP butnot with another known EAE autoantigen.The authors suggest that combining this tech-nique with Foxp3 transduction could be usedto generate a population of antigen-specificT

Regcells from the peripheral-blood T cells of

a patient.Kirsty Minton

References and linksORIGINAL RESEARCH PAPERS Jaeckel, E., von Boehmer, H.& Manns, M. P. Antigen-specific FoxP3-transduced T-cells cancontrol established type 1 diabetes. Diabetes 54, 306–310(2005) | Mekala, D. J. & Geiger, T. L. Immunotherapy ofautoimmune encephalomyelitis with re-directed CD4+CD25+

T-lymphocytes. Blood 4 Nov 2004 (doi:10.1182/blood-2004-09-3579).

Why is it that normal individuals can harbourautoreactive T cells yet do not develop overtautoimmune disease? A recent reportpublished in Nature Medicine provides apotential explanation for this conundrumand indicates that Toll-like receptor (TLR)ligation is required to cause destruction ofpancreatic islet β-cells by autoreactive T cellsin a mouse model of diabetes.

Zinkernagel and colleagues studied theRIP–GP mouse model of diabetes, in whicha lymphocytic choriomeningitis virus(LCMV) glycoprotein (GP) transgene is expressed under the control of the ratinsulin promoter (RIP). LCMV infection ofthese mice induces the clonal expansion ofLCMV-GP-specific CD8+ T-cellpopulations and the development ofhyperglycaemia. However, if RIP–GP micewere immunized with an LCMV-GP-derived peptide (gp33) together with CpG-containing oligodeoxynucleotides (to deliver co-stimulation), they did notdevelop diabetes, despite having large

numbers of fully functional gp33-specificCD8+ T cells. The absence of disease wasnot a consequence of inefficient T-cellmigration to the pancreas, as in mice thatco-express LCMV-GP and the chemokineCXCL13 in the pancreas, gp33-specificCD8+ T cells infiltrated the pancreatic isletsin response to immunization with gp33,yet these mice did not develop diabetes.Next, the authors observed that LCMVinfection, but not gp33 immunization,increased the level of serum interferon-α(IFN-α), which upregulated MHC class Iexpression by β-cells. Pancreatic MHCclass I expression could also be induced byadministration of the TLR3 ligand polyI:Cor the TLR7 ligand R848 to wild-type mice,and when administered to RIP–GP micethat were pre-immunized with gp33,hyperglycaemia developed. The ability of TLR ligands to induce disease wasdependent on expression of the type I IFN receptor, indicating that expression of MHC class I in the pancreas in response

to TLR-induced IFN-α production rendersthe pancreas susceptible to attack byautoreactive T cells.

Lucy BirdReferences and links

ORIGINAL RESEARCH PAPER Lang, K. S. et al. Toll-like receptor engagement converts T-cell autoreactivity into overt autoimmune disease. Nature Med. 11, 138–145(2005).

TLR signals provide the missing factor

A U TO I M M U N I T Y

A step closer to the clinic

R E G U L ATO R Y T C E L L S

R E S E A R C H H I G H L I G H T S

As the concept of regulatory T (TReg

) cells has become widely accepted during the past ten years, there has been increasinginterest in their thera-peutic potential toinhibit inappropriateimmune responses,such as autoimmunediseases. However, thelow frequency andunknown specificity ofnaturally occurringCD4+CD25+ T

Regcells

limit their immediate application.These two papers show how theseproblems might be overcome intwo animal models of autoimmunity— type 1 diabetes and experimentalautoimmune encephalomyelitis (EAE; amodel of multiple sclerosis).

Jaeckel et al. show that, rather thanisolating the small numbers of naturallyoccurring T

Regcells from a patient, trans-

duction of abundant naive CD4+ T cells