Why are some mouse strains susceptible to autoimmune disease, while others are resistant? Previous studies have suggested that resistance to experimental autoimmune encephalomyelitis (EAE) lies in a T-cell-specific defect. However, Kuchroo and colleagues, reporting in The Journal of Clinical Investigation, propose an alternative mechanism involving impaired activation of antigen-presenting cells (APCs) in resistant mouse strains.

SJL mice that express a transgenic T-cell receptor (TCR) specific for the myelin antigen proteolipid protein (PLP) (5B6 TCR-transgenic mice) readily develop spontaneous EAE. However, 5B6 TCR-transgenic mice on the B10.S background rarely develop spontaneous EAE. By comparing these mouse strains, the authors showed that resistance was not due to deletion of autoreactive T cells or to T-cell anergy, as both strains had comparable numbers of PLP-specific T cells, which proliferated in response to PLP peptide presented by artificial APCs in vitro. By contrast, analysis of APCs from the two mouse strains showed that those from resistant B10.S mice expressed lower levels of MHC class II and co-stimulatory molecules, and were less efficient at stimulating proliferation of transgenic T cells, indicating that B10.S APCs have a defective activation status.

The authors then went on to show that this defective APC phenotype could be overcome by incubating the cells with oligodeoxynucleotides containing CpG motifs (CpG ODNs), which have been shown to activate APCs through Toll-like receptor 9 (TLR9). Moreover, administration of CpG ODNs, but not non-CpG-containing ODNs, to EAE-resistant mice was sufficient to break T-cell tolerance and induce EAE in these mice. Co-administration of CpG ODNs and the cognate PLP peptide further increased the incidence and severity of disease in the B10.S transgenic mice. This disruption in tolerance was most readily seen when APC activation was mediated through TLR9, because administration of lipopolysaccharide, which is recognized by TLR4, did not have such a marked effect on EAE induction in the resistant strain.

So, the authors suggest that activation of APCs through receptors of the innate immune system can tip the balance between peripheral tolerance and autoimmunity in favour of autoimmune disease.