In Brief

Autoimmunity

TLR ligands are not sufficient to break cross-tolerance to self-antigens. Hamilton-Williams, E. E. et al. J. Immunol. 174, 1159–1163 (2005).

The presence of autoreactive T cells in individuals who do not have autoimmune disease shows that this is not sufficient for the induction of pathology. This paper looked at the potential role of Toll-like receptor (TLR) ligation in providing non-specific inflammatory signals that are required to turn potential autoreactivity into overt disease. Transgenic mice expressing ovalbumin in pancreatic β-cells under control of the rat insulin promoter (RIP-mOVA mice) do not develop diabetes when injected with OVA-specific CD8⁺ T (OT-I) cells in the absence of specific CD4⁺ T-cell help, owing to T-cell deletion by cross-tolerizing dendritic cells (DCs). When these mice were also injected with ligands for TLR2, TLR3, TLR4 or TLR9, which could activate the DCs for cross-priming, the OT-I cells were still deleted unless OVA-specific CD4⁺ T (OT-II) cells were added. Therefore, TLR ligation alone is not sufficient to break tolerance in this model, which is supported by the fact that infection with TLR-ligand-bearing pathogens does not commonly result in autoimmunity. This is in contrast to a recent study in Nature Medicine by Lang et al. (11, 138–145 (2005); covered as a highlight in the February issue of Nature Reviews Immunology), which showed that TLR ligation could convert the presence of autoreactive T cells into autoimmune disease in another transgenic mouse model of diabetes, through upregulation of MHC class I expression on the target organ by interferon-α produced in response to TLR stimulation. The difference between these studies could relate to the requirement for CD4⁺ T-cell help to prevent deletion of CD8⁺ T cells in the former model but not in the latter.

Regulatory T cells

Contact-mediated suppression by CD4⁺CD25⁺ regulatory cells involves a granzyme B-dependent, perforin-independent mechanism. Gondek, D. C. et al. J. Immunol. 174, 1783–1786 (2005).

The in vitro suppressive function of CD4⁺CD25⁺ regulatory T (T_Reg) cells is contact dependent, and cross-linking of glucocorticoid-induced tumour-necrosis factor (TNF)-receptor-related protein (GITR) on T_Reg cells abrogates this. Using DNA-microarray analysis, Gondek et al. showed that stimulation of T_Reg cells solely through the T-cell receptor increased levels of granzyme B cDNA but that concomitant GITR signalling markedly diminished such upregulation. Functionally, T_Reg cells isolated from granzyme-B-deficient mice were impaired in their ability to suppress in vitro CD4⁺CD25⁻ T-cell proliferation. However, the suppressive function of T_Reg cells was perforin independent, so the mechanism by which granzyme B affects T_Reg-cell-mediated suppression remains unclear. Interestingly, T_Reg cells induced CD4⁺CD25⁻ T-cell apoptosis, so further studies will aim to define the molecular link between T_Reg-cell production of granzyme B and CD4⁺CD25⁻ T-cell apoptosis.