T cell responses: a feedback mechanism

Suppression of Cytotoxic T Cell Functions and Decreased Levels of Tissue-Resident Memory T Cells during H5N1 Infection

T cells are, broadly, divided into two main subsets, those expressing CD4 and those expressing CD8. The first are helper T cells (Th); they help many other immune cells to perform better. The latter are cells that can directly kill infected cells, then called cytotoxic T lymphocytes (CTLs).

A virus infection induces a strong T cell response. In the case of a virus; a type-1 response: involving Th1 cells (CD4) and CD8 T cells. These cells are known to make the cytokine interferon-gamma (IFNg). They express activation markers, including CD25, but also PD-1, and TIM-3.

When there is a heavy infection, there is a feedback mechanism. The T cells can now express interleukin-10 (IL-10). IL-10 is an inhibitory cytokine, which will dampen the response to try and limit immune-induced pathology/damage. This is observed in many type-1 infections, such as SARS here above, and for the Malaria-causing parasite plasmodium here, where the IL-10 can also cause loss of the control of the lung microbiota. This loss of control can contribute to secondary infections. These secondary infections are well-known to play a role in influenza infections, where many patiënts do not die of influenza virus only, but of secondary bacterial or fungal infections. 

As is also described here in this paper,
"Suppression of Cytotoxic T Cell Functions and Decreased Levels of Tissue-Resident Memory T Cells during H5N1 Infection".

But some will be fooled by reading the title only. What the paper shows in mice is a heavy H5N1 infection; strong T cell activation, PD-1 is expressed, and yes, the cells express IL-10: they are highly stimulated. This does not mean the response to influenza itself is per se suppressed: it is a attempt to spare further lung damage and is normal. It does come at the cost of slower viral clearance: but that is offset against not damaging your lungs too much! An excellent deal.

Indeed, subsequent infection with a slightly different influenza virus, which shares antigens, shows that the response is robust and protects the mice very well against reinfection. This is also what the authors report.

The reason is that although the response is purposely curtailed to reduce damage, and consequently the virus is cleared later, and you make fewer memory T cells. But you do make good amounts of memory T cells that rapidly expand when needed and are particularly good at killing.

What this means is, the immune response is purposely blunted; it results in slower viral clearance, a less robust response and less memory T cells, but also less lung damage! Subsequent challenge with a remarkably similar virus for which memory T cells are protective, shows also no subsequent negative impact.