The main focus of the Jagannathan lab has been studying mechanisms driving naturally acquired immunity to malaria. Children living in malaria endemic settings eventually develop “clinical” immunity to malaria – defined as an increasing proportion of Plasmodium falciparum (Pf) infections that are asymptomatic, although mechanisms driving this protection remain unclear.
γδ T cells
We found that a subset of malaria-responsive, semi-innate γδ T cells are associated with protection from Pf infection (Figure 2). However, repeated malaria in children is associated with loss and dysfunction of these inflammatory T cells. Furthermore, loss and dysfunction of these cells is associated with a reduced likelihood of symptoms upon subsequent Pf infection, suggesting immunologic tolerance of the parasite.
We are actively studying how malaria drives innate immune dysfunction by studying the impact of in vivo and in vitro malaria infection on innate immune epigenetics, transcriptomics, and cellular function.
Researcher: Kassie Press
CD4+ T cells
We are in particular interested in how repeated malaria modulates the innate immune response and malaria-specific CD4+ T helper cells. We are also leveraging high-throughput sequencing approaches and pioneering new experimental and computational methods to study CD4+ T cell immunology and Pf-specific responses of these cells. Ongoing projects in the lab entail modeling CD4+ T cell epigenetics and clonal dynamics in children as they experience multiple Pf infections. Through this unique longitudinal study design, we hope to elucidate the role of CD4+ T cells in the acquisition of clinical immunity while also uncovering new biology with respect to memory recall responses and their heterogeneity within the CD4+ T cell compartment.
Researcher: Jason Nideffer
NK cells
Natural Killer (NK) cells likely play an important role in immunity to malaria, but whether repeated malaria modifies the NK cell response remains unclear. We found that repeated malaria exposure was associated with expansion of an atypical, CD56neg population of NK cells that differed transcriptionally, epigenetically, and phenotypically from CD56dim NK cells, including decreased expression of PLZF and the Fc receptor g chain, increased histone methylation, and increased protein expression of LAG-3, KIR and LILRB1. CD56neg NK cells were highly functional, displaying greater antibody dependent cellular cytotoxicity than CD56dim NK cells, and higher frequencies of these cells were associated with protection against symptomatic malaria and high parasite densities. Importantly, following marked reductions in malaria transmission, frequencies of these cells rapidly declined, suggesting that continuous exposure to malaria is required to maintain this modified, adaptive-like NK cell subset.
Researchers: Maureen Ty, Savannah Lewis
