Science Editor

In experiments that could ultimately bear practical fruit for the treatment of both cancer and autoimmune disorders, scientists have discovered that hypoxia inducible factor, or HIF-1, plays a major role in determining whether T cells develop into pro-inflammatory TH17 cells or regulatory T cells, which inhibit the actions of other T cells and prevent the immune response from going out of control.

T cells, senior author Fan Pan told BioWorld Today, "develop from the same pool of precursor cells" into one of four possible types.

Broadly speaking, TH1 cells take care of bacterial and viral infections; TH2 cells are more active in fighting parasitic infections; and TH17 cells appear to protect against bacteria and viruses at the skin surface, but they also play a big role in autoimmune diseases like multiple sclerosis. Regulatory T cells, which are slower to develop than the other T cell types, help end the immune response to infections.

Which T-cell type a precursor cell will turn into depends partly on its microenvironment during development, including which cytokines it is exposed to. But many of the details remain to be worked out. Exposure to TGF-beta, for example, can result in either a TH17 cell or a regulatory T cell.

In the Aug. 26, 2011, issue of Cell, Pan, who is an assistant professor of immunology at Johns Hopkins University, and his colleagues reported the involvement of a transcription factor in T-cell development that is better known for its connections to metabolism: HIF-1-alpha.

HIF is in the sights of several biopharmaceutical companies for its role in promoting angiogenesis. It also regulates metabolism, coordinating changes in metabolism to help cells adapt to conditions of low oxygen.

But Pan and his colleagues found that HIF-1-alpha is important for T-cell development whether oxygen levels are low or not.

In cell culture experiments, the authors found that HIF-1 favors the development of pro-inflammatory TH17 cells over regulatory T cells in two separate ways.

First, HIF-1 promoted the development of TH17 cells through its interactions with a nuclear hormone receptor, ROR-gamma T, which activated a gene expression program typical of TH17 cells.

The transcription factor also actively inhibited the development of regulatory T cells by binding to Foxp3, a protein that normally promotes regulatory T cell development, and marking it for destruction by the proteasome.

Finally, Pan and his team looked at knockout mice that had no HIF-1 in their T cells. Those animals had fewer TH17 and more regulatory T cells than their wild-type cousins, and when the authors attempted to induce autoimmune encephalitis, the mouse equivalent of multiple sclerosis, knockout mice were "highly resistant" to developing the disease.

HIF-1-alpha exerted its effects not just when oxygen was low. But the findings provided a further clue to cancer and inflammation.

Low oxygen, which is a prominent feature of tumors once they have grown beyond a certain size, would increase HIF activity and that would be especially favorable to the development of pro-inflammatory TH17 cells.

HIF-1 is, at least in principle, a druggable target, and Pan said his team's findings could be brought to bear both on autoimmune disease and cancer.

Inhibiting HIF-1 tips the balance away from regulatory T cells, which could be useful in cancer immunotherapies. Some successes notwithstanding, cancer immunotherapies as a whole still struggle to overcome immune inhibitory mechanisms that are meant to prevent autoimmune diseases but can help cancer cells escape immune surveillance. Several HIF inhibitors already are being developed clinically as cancer therapies, and the new study suggested an additional rationale for how and why such inhibition might work.

On the other hand, activating HIF-1 could prove useful in autoimmune disorders by slowing down the development of TH17 cells.

Activators are more challenging to develop than inhibitors, and in combination with the fact that the idea that HIF is linked to T-cell development is itself "a very novel concept," any practical applications in the area of autoimmunity are further in the future.

But given that TH17 cells are "clearly involved" in diseases like Crohn's disease and autoimmune encephalitis, and his team's results showing that HIF-1 knockouts are resistant to the development of autoimmune encephalitis, Pan contended that this avenue, too, is at least worth pursuing.