gms | German Medical Science

A balance between pro- and anti-inflammatory mechanisms is crucial for an optimal immune response following an infection with the human malaria pathogen Plasmodium falciparum (Pf). However, the machanisms behind this balance are still inadequately understood. It has been shown that, in murine malaria models, T cells activation is influenced by regulatory T cells as well as coinhibitory receptors such as CTLA-4 and PD-1 expressed on effector cells. However, the precise function of the different coinhibitory receptors in human Pf malaria is unknown at the moment.

In order to clarify the role of coinhibitory molecules in Pf malaria, peripheral blood from voluntary donors with imported Pf malaria was analyzed for expression of coinhibitory molecules and effector functions of T effector cells using flow cytometry. Some patients could be monitored at several time points from admission to hospital until recovery to establish a kinetic analysis of the expression pattern of these molecules over the course of the disease. Our experiments showed an induction of the coinhibitory molecules PD-1, CTLA-4, LAG-3, and TIM-3 on CD4⁺ T cells in human Pf malaria. Interestingly, the majority of coinhibitor-positive cells coexpress several molecules at the same time. Expression of the coinhibitory molecules persists even after clearance of the parasite while the aforementioned molecules show different patterns of downregulation. Furthermore, coinhibitor-positive CD4⁺ T cells exhibit an altered phenotype concerning effector functions during the disease, expressing Granzyme B and CD39.

These results demonstrate that, besides PD-1 and CTLA-4, additional coinhibitory molecules like LAG-3 and TIM-3 play an important role in T cell modulation in human Pf malaria and might contribute to the immunological balance between clearance of the pathogen and prevention of an excessive immune response.