A new role for interleukin‐10 in immune regulation

Interleukin-10 (IL-10) is well characterized as an anti-inflammatory cytokine, with potent suppressive effects in preventing autoimmune disease.1 In the absence of IL-10, spontaneous mucosal autoimmunity develops, while the effect on systemic autoimmunity is far more muted.2 In this issue of Immunology and Cell Biology, however, Lesage and colleagues3 have uncovered an extra layer of complexity to the role of IL-10 in immune regulation. Lesage and colleagues use a T-cell receptor transgenic system to track autoreactive T cells, specific for a pancreatic neo-antigen, that develop into CD4−CD8− ‘double negative’ (DN) T cells. These cells have the capacity to specifically lyse B cells loaded with neo-self antigens.3 In a physiological setting, this is likely to reflect the suppression of autoreactive B cells that have internalised and presented the pancreatic self antigen. The antigen-specific activity of the DN T cells makes them particularly attractive as potential therapeutic mediators. Although autoimmune diabetes is not often thought of as an antibody-mediated disease, antibodies towards proinsulin predate and predict progression to clinical diabetes,4 and anti-CD20 antibody-mediated B cell depletion shows some promise as a treatment.5 The physiological relevance of DN T cells in autoimmune diabetes was previously demonstrated by the same group, as autoimmune-prone non-obese diabetic mice have a reduced number of DN T cells, and passive transfer of DN T cells prevents diabetes progression.6 In this most recent advance, Hillhouse et al.3 analysed the molecular basis for reduced DN T-cell numbers in non-obese diabetic mice. The authors found that ex vivo non-obese diabetic DN T cells have a 10-fold increase in IL-10 expression. In vitro, IL-10 had no impact on DN T-cell function or proliferation, but greatly accelerated apoptosis. This new role for IL-10 is in contrast to its previously defined immunosuppressive roles, against both TH1 and TH2 immune responses. Although most cell types of both the adaptive and innate immune systems are capable of expressing IL-10 to various degrees, the key producers are Foxp3+ regulatory T (TREG) cells. The mucosal autoimmunity that occurs in IL-10-deficient mice is essentially replicated by Foxp3+ TREG cell-specific ablation of IL-10.7 This suggests that alternative sources of IL-10 production are of secondary importance in mucosal tolerance, although it does not exclude important roles for IL-10 derived from other sources under specialised conditions. IL-10 also further promotes its own production as well as the function of TREG cells, initiating a positive feedback loop for immune suppression via this key regulatory T-cell subset.8 As DN T cells are suppressed via exposure to IL-10, this gives IL-10 opposing functions—amplifying one regulatory T cell population while actively suppressing another (Figure 1). These results, although surprising, potentially explain several discrepancies in the literature on IL-10. Although considered to be immunosuppressive in function, the use of IL-10 as a potential therapeutic has given mixed results, suggesting a more complex role in immune regulation. The effect of IL-10 on B cells, in particular, may be stimulatory rather than suppressive, as IL-10 enhances immunoglobulin production and elevates MHC class II expression on B cells.9, 10 Although the stimulatory capacity may be relatively weak, especially in mouse B cells compared with human B cells,9, 10 the upregulation of MHC class II may necessitate a form of protection against DN T cells, which lyse B cells through MHC class II recognition.3 The effect of IL-10 on B cells may therefore constitute both a direct stimulatory effect and an indirect protection from DN T cells, to allow effective stimulation of antibody responses. In the case of autoimmune diabetes, both modes of IL-10 activity may be active. Systemic treatment with IL-10 through transgenic expression or subcutaneous injection protects against autoimmune diabetes.11, 12 By contrast, transgenic expression of IL-10 in the pancreatic islets precipitates autoimmune diabetes, even on a resistant genetic background, and treatment with anti-IL-10 antibodies inhibits insulitis in non-obese diabetic mice.13 Together, these findings suggest that systemic IL-10 has a net immunosuppressive function, possibly through the promotion of Foxp3+ TREG-mediated suppression, whereas local IL-10 production has a net immunostimulatory activity potentially through the amplification of DN T cell apoptosis (Figure 2). Notably, the location of the primary function of each regulatory cell type may be the inverse of the location where IL-10 has its primary effect. That is, Foxp3+ TREG cells are of the greatest importance in suppressing autoreactive T cells within the inflamed islet,14 whereas the greatest effect of DN T cells on autoreactive B cells is presumably within the draining lymphatics. If this model is correct, the timing and localization of IL-10 delivery during therapeutic treatment will be key to determining whether a beneficial or detrimental impact is achieved. The authors declare no conflict of interest.