A TCRβ Repertoire Signature Can Predict Experimental Cerebral Malaria

Abstract

Cerebral Malaria (CM) is associated with a pathogenic T cell response. Mice infected by P. berghei ANKA clone 1.49 (PbA) developing CM(CM+) present an altered PBL TCR repertoire, partly due to recurrently expanded T cell clones, as compared to non-infected and CMinfected mice. To analyse the relationship between repertoire alteration and CM, we performed a kinetic analysis of the TRBV repertoire during the course of the infection until CMrelated death in PbA-infected mice. The repertoires of PBL, splenocytes and brain lymphocytes were compared between infected and non-infectedmice using a high-throughput CDR3 spectratyping method. We observed a modification of the whole TCR repertoire in the spleen and blood of infected mice, fromthe fifth and the sixth day post-infection, respectively, while only three TRBV were significantly perturbed in the brain of infectedmice. Usingmultivariate analysis and statistical modelling, we identified a unique TCRâ signature discriminating CM+ from CTR mice, enriched during the course of the infection in the spleen and the blood and predicting CM onset. These results highlight a dynamic modification and compartmentalization of the TCR diversity during the course of PbA infection, and provide a novel method to identify disease-associated TCRâ signature as diagnostic and prognostic biomarkers.