Pathogenic low affinity CD8 T cells in malaria

The focus of the research in the Lamb lab is to determine mechanisms of the immunopathogenesis of malaria. The Evavold lab is one of the leading laboratories working in T cell biology with the capability to precisely measure the affinity profile of polyclonal T cell populations. Together we will address the long-term goal of this proposal which is to define the salient features of the T cell response during Plasmodium infections that drives the pathology of malaria. It is estimated that annually more than 500 million people are infected with malaria worldwide resulting in 0.5 million deaths. T cell responses against the Plasmodium parasites that cause malaria are critical in orchestrating immune effector mechanisms such as phagocytosis and antibody production to control parasitemia. However, T cells are also responsible for the pathogenesis of infection. The features that determine beneficial versus pathogenic T cells in malaria are incompletely understood. Here we propose that the affinity of CD8 T cells reacting to Plasmodium peptides shapes the repertoire of expanded cells and profoundly alters their function, in turn impacting pathogenesis. Although others have identified T cell epitopes that are immunodominant in Plasmodium infections, we know very little about the antigen reactivity profile of these pathogenic T cells as infection progresses. In general, it is believed that high affinity T cells predominate any polyclonal T cell response, yet this is not supported by our preliminary data which clearly shows that low affinity T cells make up >80% of the pathogenic anti-Plasmodium response. Based on our preliminary data, we hypothesize that this predominance of low affinity CD8 T cells is a unique feature of Plasmodium infection that leads to organ specific damage because CD8 T cells with low affinity T cell receptors induce different responses in cross-presenting brain microvascular endothelial cells (BMECs) compared with high affinity CD8 T cells. The rationale for the proposed work is that T cell responses are central to the organ-specific attack associated with malaria, and a more comprehensive understanding of the T cell response will provide key information for the rational use and design of novel anti-malaria interventions as well as future vaccines. We plan to test our central hypothesis and, thereby, accomplish the objective of this application, by pursuing the following three specific aims: Aim 1: Demonstrate that low affinity CD8 T cells are pathogenic in experimental cerebral malaria Aim 2: Define the functional differences between low and high affinity CD8 T cells trafficking to the CNS in Plasmodium infection Aim 3: Test the hypothesis that low affinity CD8 T cells predominate the response based on the context of how the parasite antigens are recognized.