title: Dynamics of the human T cell response to repeated immunization with irradiated malaria parasites
creator: Bartsch, Ilka Maria
subject: ddc-570
subject: 570 Life sciences
description: Plasmodium falciparum (Pf) is a unicellular parasite and the major causative agent of human malaria. The sporozoite form of the parasite is transferred from mosquitos to humans and can infect hepatocytes in the liver. Both Pf-specific antibodies, generated with the help of CD4+ T follicular helper cells, and CD8+ T cells can limit disease progression at an early stage by preventing the infection of hepatocytes and eliminating infected cells, respectively. However, so far no vaccine is capable of eliciting strong humoral and cellular immune responses that can reliably confer long-term protection. Therefore, a better understanding of immune responses induced by current vaccines is necessary to guide the development of alternative vaccination strategies. While many studies focused on the evolution of protective B cell responses during malaria immunizations, little is known about the kinetics of emergence and maintenance of T cell subsets. In this study, a newly developed platform for the single-cell, high-throughput sequencing and expression-cloning of human T cell receptors (TCRs) was applied to characterize the TCR repertoire of CD8+ effector memory T (TEM) cells and CD4+ circulating T follicular helper (cTFH) cells induced during immunization with radiation-attenuated sporozoites (Pf RAS). This study revealed that the two subsets show contrary dynamics in their repertoire upon immunization. In activated CD8+ TEM cells, the repertoire was dominated by large, persistent clones which did not respond to Pf RAS immunization. The recruitment of smaller, highly diverse clones of yet unknown specificity resulted in the diversification of the repertoire upon immunization. In contrast, in the cTFH cell compartment the Pf RAS immunization led to the clonal expansion of activated cells, which dominated the otherwise highly polyclonal repertoire. The activated cTFH cells were highly enriched for clones reacting to the C-terminal region of the circumsporozoite protein (C-CSP), the most abundant protein on the surface of sporozoites. While most of the C-CSP-reactive cTFH cells carried diverse TCRs, some formed clusters of highly similar TCRs that could be detected within but also between donors, indicating convergence in the otherwise highly diverse TCR repertoire. Identification of epitopes targeted by the Pf-specific TCRs could complement the information about the dynamics of Pf-specific clones and would thereby provide helpful insight into how different T cell epitopes shape the T cell repertoire during immunizations. This information could help to optimize existing vaccines, e.g. by reducing subunit vaccines to epitopes which dominate the Pf-specific T cell responses and are highly conserved between Pf strains, thereby enhancing protection from heterologous infection.
date: 2021
type: Dissertation
type: info:eu-repo/semantics/doctoralThesis
type: NonPeerReviewed
format: application/pdf
identifier: https://archiv.ub.uni-heidelberg.de/volltextserverhttps://archiv.ub.uni-heidelberg.de/volltextserver/28902/1/Ilka_Bartsch_PhD_Thesis.pdf
identifier: DOI:10.11588/heidok.00028902
identifier: urn:nbn:de:bsz:16-heidok-289025
identifier:   Bartsch, Ilka Maria  (2021) Dynamics of the human T cell response to repeated immunization with irradiated malaria parasites.  [Dissertation]     
relation: https://archiv.ub.uni-heidelberg.de/volltextserver/28902/
rights: info:eu-repo/semantics/openAccess
rights: http://archiv.ub.uni-heidelberg.de/volltextserver/help/license_urhg.html
language: eng