A contrarian view of how the immune system controls virus infections

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TCR independent suppression of CD8+ T cell cytokine production mediated by IFNγ in vivo

Text by J. Lindsay Whitton

Viruses survive and grow inside cells. The immune system has evolved to counter these infections using several strategies, two of which are (i) killing the infected cells (thus also killing the viruses that they contain) and (ii) showering nearby uninfected cells with specialized molecules (termed cytokines), which cause those cells to become more resistant to virus infection. One such cytokine, interferon gamma (IFNγ), produced mainly by T cells and natural killer (NK) cells, is thought to play a key role, not only by limiting the spread of virus to uninfected cells but also by eradicating intracellular viruses without killing the cells. One might predict that such a powerful antiviral molecule would be abundantly and continually produced until the virus infection was under control. However, in our study, we found that IFNγ production by immune cells is extremely short-lived, terminating long before the virus infection has been completely cleared. Moreover, we showed that IFNγ can inhibit its own subsequent production, suggesting that IFNγ released from one immune cell may prevent neighboring immune cells from producing this cytokine.

These unexpected observations have led us to entertain the notion that IFNγ might not be critically important for directly controlling many virus infections. This flew in the face of current dogma, so we were, initially, hesitant to pursue this hypothesis. However, its potential validity has been supported by work from other labs that demonstrated that human patients with genetic defects in the IFNγ signaling pathway can cope perfectly well with the vast majority of virus infections. So, at least in humans, IFNγ is not required for the control of viruses.

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Figure legend

The possible means by which IFNγ acts during virus infection are shown in the diagram. Current understanding states that (arrow #1) IFNγ can act directly on virus-infected cells e.g., cells in the liver, heart, or pancreas (or most other tissues) to control the infection. However, as stated above, our data, and data from humans with genetic abnormalities, demonstrate that this direct effect – if it occurs – is not required for the ultimate clearance of virus. We currently favor the idea that any antiviral role of IFNγ is likely to be indirect, mediated by the cytokine acting on immune cells (#2), causing them to increase in number (#3); and these more abundant immune cells then clear the virus, perhaps in an IFNγ-independent manner (#4).

Introducing the authors

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Martin Hosking (left) is a former postdoctoral colleague of Dr. J Lindsay Whitton (middle), whose lab studies viral pathogenesis, immunology, and vaccines. Claudia Flynn (right) is a Senior Research Associate in the lab.

About the research

TCR independent suppression of CD8+ T cell cytokine production mediated by IFNγ in vivo
Martin P. Hosking, Claudia T. Flynn, J. Lindsay Whitton
Virology, Volume 498, November 2016, Pages 69–81