Although our projects are largely focused on the study of innate and adaptive immune cells that orchestrate immunity against Plasmodium infection and malarial disease, our experiments are directly relevant to chronic inflammatory pathologies caused by other eukaryotic pathogens, viruses, and bacteria, and specific cancerous tumors. Our overarching goals are to define key molecular pathways that regulate the activity of T and B lymphocytes responding to medically relevant immunological insults.
Development and Function of Plasmodium-specific memory CD4 T cells:
Sterilizing immunity against Plasmodium rarely develops in humans, even following repeated parasite exposure. We are testing the hypothesis that Plasmodium-specific memory CD4 T cell responses are functionally deficient, thus explaining weak and short-lived cellular and antibody immunity against this infection. Resolving bystander from bona fide Plasmodium-specific memory CD4 T cells remains a significant technical hurdle to studying immune memory and protection against malaria. Our lab has developed and is applying new methods and powerful immunologic, genetic, and biochemical approaches to ‘see’ and study Plasmodium-specific memory CD4 T cell populations. These approaches position us to directly test our hypotheses about the induction, regulation, maintenance, and function of parasite-specific effector and memory CD4 T cell populations.
Regulation of Plasmodium-specific effector CD4 T cell function:
Immune-mediated resistance to blood stage Plasmodium infection requires effective CD4 T cell and B cell communication and the induction of protective antibody secretion. We have identified that both human and experimental malaria engage both co-stimulatory and co-inhibitory pathways that act as rheostats to “fine-tune” pathogen-specific CD4 T cell activity. We are interested in determining the relevance and utility of therapeutically targeting these cell surface immuno-regulatory receptors and their ligands to improve CD4 T cell and B cell communication and the stimulation of long-lived, antibody-mediated immunity. Extensions of these projects employ intravital and two-photon microscopy to study the spatial relationships between parasite-specific immune cell subsets. We are also examining the role and function of specific adaptor proteins that transduce signals from the cell surface to activate specific transcriptional networks in Plasmodium-specific T cells and B cells.
Transcriptional and epigenetic regulation of helper T cell differentiation:
Following infection or vaccination, functionally distinct CD4 T cell subsets that include Th1, Tfh, Th17, and CD4+ CTL differentiate from naïve precursor populations after receiving specific “cues” during their activation. These programming events include the secretion of cytokines and provision of co-stimulation by antigen presenting cells. We have multiple studies underway to dissect “when and how” these stimuli program the differentiation and function of Plasmodium-specific effector and memory T cells. We are applying powerful conditional knockout and reporter systems to define the molecular and transcriptional circuits that govern these processes during Plasmodium infection.
The induction and activity of regulatory lymphocytes during malaria:
The mobilization and function of regulatory populations of T and B cells are critical for limiting excessive lymphocyte activation and immunopathology following infection. However, many pathogens, including malaria parasites, appear to have evolved mechanisms to exploit these regulatory circuits, which ultimately facilitates their capacity to establish chronic infection and subvert the development of long-lived, protective immunity. We have multiple projects that are focused on dissecting both host- and parasite-specific factors that mobilize regulatory cells and identifying the mechanisms by which regulatory cells can impair anti-parasite immunity during Plasmodium infection.