Linking integrins, TGFβ and autoimmunity

Transforming growth factor-β (TGFβ), partly through its induction of regulatory T cells, has a crucial role in maintaining immune homeostasis. However, TGFβ must be activated to exert its regulatory effects, and the exact mechanisms involved in its activation and function in vivo are controversial. Now, Travis and colleagues show that the loss of TGFβ-activating α_Vβ₈-integrin in dendritic cells (DCs) results in severe inflammatory bowel disease and autoimmunity in mice, indicating an important role for α_Vβ₈-integrin in the prevention of immune dysfunction.

...loss of TGFβ-activating α_Vβ₈-integrin in dendritic cells (DCs) results in severe inflammatory bowel disease and autoimmunity...

Previous studies have shown that the complete loss of β₈-integrin (encoded by Itgb8 ) expression in mice is lethal, so the authors generated mice with a conditional deletion of Itgb8 in leukocytes. By 10 months of age, all surviving mice developed severe colitis and had high levels of circulating autoantibodies. These mice also had higher numbers of peripheral activated or memory T cells that expressed interleukin-4 and interferon-γ, and increased serum IgE, IgA and IgG1 levels compared with control mice. The phenotype of these mice is almost identical to the phenotype of mice that lack key elements of the TGFβ signalling pathway, indicating that α_Vβ₈-integrin has an important role in activating TGFβ in vivo.

To identify the exact subset of leukocytes involved, mice were generated that specifically lacked β₈-integrin expression in T cells or in DCs. Mice with a conditional loss of β₈-integrin expression in T cells were phenotypically indistinguishable from control mice, whereas mice with a conditional loss of β₈-integrin expression in DCs were identical to mice that lacked β₈-integrin expression in all leukocytes. Further in vitro analysis showed that although the lack of β₈-integrin expression did not affect the maturation of DCs, the ability of these DCs to convert CD4⁺ T cells into regulatory T cells — as determined by their expression of forkhead box P3 (FOXP3)— was greatly reduced. However, the addition of active TGFβ to in vitro co-cultures restored the induction of regulatory T cells by β₈-integrin-deficient DCs. Interestingly, the percentage of FOXP3⁺ regulatory T cells in the spleens of mice with β₈-integrin-deficient DCs was the same as that in control mice. However, there was a 50% reduction in the percentage of regulatory T cells in colonic lamina propria of these deficient mice relative to control mice.

Taken together, the data indicate an important role for α_Vβ₈-integrin-mediated TGFβ activation and the subsequent induction of regulatory T cells in the maintenance of immune homeostasis in the colon, disruption of which results in autoimmunity and inflammatory bowel disease.