Marking of cytotoxic T cells (CD8 in red and the ‘residence’ marker CD103 in green) lodged in the choroid plexus of a brain infected with the parasite Toxoplasma gondii. © Amel Aida

Toxoplasmosis is an infection caused by the parasite Toxoplasma gondii (T. gondii). In over one third of the human population, this parasite establishes a chronic infection of the brain which can have serious consequences in people with compromised immunity. Given the current lack of treatment to eliminate the persistent form of the parasite, a deeper insight into the immune mechanisms controlling this infection is essential if we are to hope to develop new therapeutic strategies. The study, conducted by Inserm researcher Nicolas Blanchard and his team at the Toulouse Institute for Infectious and Inflammatory Diseases (Infinity, Université Toulouse III Paul Sabatier, CNRS, Inserm), has shown that a category of immune cells known as resident CD8+ T cells plays a key role in detecting and neutralising the toxoplasmosis parasite in the brain. These findings, published in PNAS, make it possible to envisage new avenues for treatments to eliminate the persistent forms of toxoplasmosis.

Toxoplasmosis is a very common parasitic infection in humans. One in three people – or even one in two in some countries – has been exposed to this parasite in their lifetime. The parasite is transmitted by direct contact with the faeces of a feline carrier of T. gondii or by eating foods contaminated with it (poorly cooked meat, raw fruit and vegetables).

The consequences of this infection vary from one person to another. In healthy people, these are usually mild: while there may be fever and fatigue, the symptoms often go unnoticed. However, the parasite is not eliminated from the body. It can persist permanently in a so-called ‘latent’ form in the muscles, retina and brain. A growing body of data suggests that this chronic brain infection is associated with behavioural changes, or even an acceleration of neurodegenerative phenomena. What is more, in people with more fragile immunity, such as those with AIDS or using certain immunosuppressive treatments (e.g. in case of transplant), the consequences can be severe because the parasite can reactivate in the brain and cause potentially fatal inflammation (called brain toxoplasmosis or neurotoxoplasmosis).

At present, there is no treatment to eliminate the persistent form and permanently remove the parasite. A better understanding of the immune mechanisms that control the parasite, particularly in the brain, could suggest new therapeutic strategies aimed at stimulating natural immunity to the parasite in order to better contain or even eliminate it. 

The research team had previously shown that specific immune cells, called CD8+ T cells or ‘killer’ T cells, play a key role in controlling the parasite in the brain. However, we are dealing with a very diverse population of cells. For Inserm researcher Nicolas Blanchard and his team, it was crucial to identify which CD8+ T-cell subtype is involved, in order to elucidate the immune surveillance mechanisms of the parasite in the brain.

In 2009, a specific subtype of CD8+ T cells, referred to as ‘resident’ CD8+ T cells, was discovered.  These cells have the particularity of not patrolling the body but remaining stationary in the tissues, particularly the brain. The role of the brain-resident CD8+ T cell subpopulations in neutralising and eliminating the parasite had never previously been studied.

To study this role, the researchers used an animal model that mimics the latent T. gondii infection found in humans. Through selective elimination of the circulating or resident subpopulations, the team showed that the parasite is controlled in the brain by resident CD8+ T cells, as opposed to the other lymphocytes that patrol the lymphoid organs and tissues.

The researchers have also shown that the resident CD8+ T cells form thanks to signals issued by other immune cells, namely CD4+ T cells.

‘This is an interesting finding because it gives us a deeper insight into why people with HIV are potentially more vulnerable to brain toxoplasmosis. Indeed, HIV is known to reduce the number of CD4+ T cells, which could have a negative impact cascade on the formation of brain-resident CD8+ T cells, and therefore alter immunity to the toxoplasmosis parasite,’ explains Blanchard.

Based on these findings, the scientists will now be able to consider strategies in an attempt to improve the capacity of resident lymphocytes to fight brain infection.

‘Now that we have a better understanding of the mechanisms of surveillance of the toxoplasmosis parasite in the brain, we are conducting other research to understand the mechanisms deployed by the parasite to evade the control by CD8+ T cells and how we can try to neutralise these mechanisms,’ concludes Blanchard.

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