Soluble Signal

An immune protein previously thought to mark inactive T cells has a free-floating form that correlates with HIV disease progression.

By | May 1, 2015

ON TARGET: A T cell expressing the protein Tim-3 (green) binds via T-cell receptors (red) to a cell targeted for destruction (blue). KIERA CLAYTON

EDITOR'S CHOICE IN IMMUNOLOGY

The paper
K.L. Clayton et al., “Soluble Tim-3 is shed from CD8+ T cells by the sheddase ADAM10, is increased in plasma during untreated HIV infection, and correlates with HIV disease progression,” J Virol, doi:10.1128/JVI.00006-15, 2015.

The molecule
The Tim-3 protein on the surface of T cells is thought to dampen the immune response to prevent harmful overactivation. But in HIV infections, this protective mechanism is hijacked to exhaust T-cell function. Previous studies had found soluble Tim-3 (sTim-3) in the blood of cancer patients, but the role of circulating Tim-3 in HIV infections was not known.

The association
Kiera Clayton and her colleagues in Mario Ostrowski’s lab at the University of Toronto, along with collaborators elsewhere, analyzed the blood of people infected with HIV and did indeed find sTim-3. Furthermore, sTim-3 levels correlated with patients’ viral load, suggesting that the protein tracks with disease progression.

T-cell surprise
Despite the prevailing view of Tim-3’s role in quieting immune activity, inhibiting T cells from shedding Tim-3 did not completely wipe out their function; in fact, some cells continued to release interferon. “Just because cells express Tim-3 doesn’t necessarily mean that they’re inactive as T cells,” indicating a surprisingly complex function of the molecule, says Lawrence Kane of the University of Pittsburgh who was not involved in the study.

Diagnosing function
The findings point to sTim-3 as a good biomarker for HIV and potentially for other chronic diseases such as cancer, says Kane. Further functional studies are necessary to determine whether disease progression relies on Tim-3, and, if so, perhaps could be slowed by lowering Tim-3 levels, says Clayton. “This does have implications in terms of treatment options.”

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