Abstract
TNF is an important inflammatory mediator and a target for intervention. TNF is produced by many cell types and is involved in innate inflammation as well as adaptive immune responses. CD8 T cells produce TNF and can also respond to TNF. Deficiency of TNF or TNFR2 has been shown to affect anti-viral immunity. However, as the complete knockout of TNF or its receptors has effects on multiple cell types as well as on lymphoid architecture, it has been difficult to assess the role of TNF directly on T cells during viral infection. Here we have addressed this issue by analyzing the effect of CD8 T cell intrinsic TNF/TNFR2 interactions during respiratory influenza infection in mice, using an adoptive transfer model in which only the T cells lack TNF or TNFR2. During a mild influenza infection, the capacity of the responding CD8 T cells to produce TNF increases from day 6 through day 12, beyond the time of viral clearance. Although T cell intrinsic TNF is dispensable for initial expansion of CD8 T cells up to day 9 post infection, intrinsic TNF/TNFR2 interactions potentiate contraction of the CD8 T cell response in the lung between day 9 and 12 post infection. On the other hand, TNF or TNFR2-deficient CD8 T cells in the lung express lower levels of IFN-γ and CD107a per cell than their wild type counterparts. Comparison of TNF levels on the TNFR2 positive and negative T cells is consistent with TNF/TNFR2 interactions inducing feedback downregulation of TNF production by T cells, with greater effects in the lung compared to spleen. Thus CD8 T cell intrinsic TNF/TNFR2 interactions fine-tune the response to influenza virus in the lung by modestly enhancing effector functions, but at the same time potentiating the contraction of the CD8 T cell response post-viral clearance.
Highlights
During an infection, the immune system must balance the need for a strong immune response against collateral damage
The results show that CD8 T cell intrinsic TNF/TNFR2 signaling has a dual role during influenza infection, in enhancing effector function per cell as measured by IFN-γ production and degranulation, as well as in potentiating the contraction of the effector response
As morbidity and viral load are similar between groups during this mild respiratory infection, this model is ideal to test the effect of T cell intrinsic TNF on CD8 T cells during the disease course, without the confounding effects of differential viral load, which can have profound impacts on T cell responses [33]
Summary
The immune system must balance the need for a strong immune response against collateral damage. This is true during respiratory infections where too strong a T cell response in the lung can cause immune pathology, but too weak a response can lead to failure to clear the infection, resulting in virus-mediated damage. Membrane TNF can trigger TNFR1 and TNFR2 signaling, whereas soluble TNF has preferential effects on TNFR1 over TNFR2 [8,9]. Since the threat of new influenza pandemics is a constant and CD8 T cells are important in controlling influenza infection when neutralizing antibody responses are absent [11,12], the need to understand the impact of TNF signaling in influenza infection is important
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