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T cell responses: a feedback mechanism

3/1/2023

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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.


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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.
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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.
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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.
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    Professor Marc Veldhoen is an immunology expert and leads the MVeldhoen lab at the Instituto de Medicina Molecular (iMM) in Lisbon, Portugal.

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