Requirements for the Induction of Adaptive Immune Responses to Rotavirus

Research output: ThesisDoctoral Thesis (compilation)

Abstract

Rotavirus (RV) infections remain the leading cause of world-wide diarrhea-associated morbidity and mortality among children <5 years of age. Despite the global introduction of RV vaccines over a decade ago, RV infections result in >200,000 deaths annually mostly in the low-income countries of Africa and Asia. Efficient clearance of the primary RV infection and protection from future re-infections is mediated by adaptive immune responses. The aim of the work presented in this thesis was to investigate the spatial, cellular and molecular requirements for the efficient induction of optimal adaptive immune responses towards primary RV infection. Intestinal RV-specific IgA is the major correlate of protection from re-infection with RV. In Paper I, we demonstrated that Batf3-dependent cDC1 but not cDC2 (specific subsets of antigen-presenting dendritic cells) are required for the optimal induction of T cell-dependent RV-specific IgA responses in the mesenteric lymph nodes (mLNs). Additionally, cDC1-driven RV-specific IgA was dependent on the selective expression of the TGFβ-activating αvβ8 integrin by cDC1 while signaling via the type I interferon receptor on the dendritic cells was dispensable. In Paper II, we investigated the major intestinal inductive site for the initiation of adaptive immune responses towards primary RV infection using lymphoid organ hypertrophy as a readout. We showed that the RV-induced hypertrophy was confined to the intestinal draining mLNs and resulted from increased recruitment of lymphocytes into the mLN and halted lymphocyte egress from the mLNs. Furthermore, the RV-induced hypertrophy of the mLNs was independent of antigen-specific recognition, type I interferon- and tumor necrosis factor α- receptor signaling. Cytotoxic CD8 T cells mediate clearance of primary RV infection. In Paper III, we addressed the role of retinioc acid (RA) signaling in the development and function of CD8 T cells. Using the CD4Cre.dnRARlsl/lsl mouse model, we showed that the absence of RA signaling in the developing thymocytes perturbed thymopoiesis and led to the accumullation of CD8SP thymocytes. Additionally, the abrogated RA signaling in peripheral CD8 T cells led to reduced expression of RA-controlled effector genes and impaired cytotoxic activity of the CD8 T cells. In Paper IV, we investigated the molecular requirements for the activation and migration of intestinal cDC1 and cDC2 in response to poly(I:C), a TLR3-targeting adjuvant. We demostrated that poly(I:C) induced both cDC1 and cDC2 activation and migration from the small intestinal lamina propria to the mLNs in a TLR3-dependent manner despite the lack of TLR3 expression by cDC2. Furthermore, both cDC1 and cDC2 migration depended on tumor necrosis factor α while cDC1 showed a unique requirement for type I interferon signaling. Collectively, the work included in this thesis helps to broaden our understanding of the requirements for the efficient induction of optimal RV-specific adaptive immune responses and provides important insights in the designing of better RV vaccines.

Details

Authors
  • Joy Nakawesi
Organisations
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Immunology in the medical area

Keywords

  • Rotavirus, classical dendritic cells, Lymphoid organ hypertrophy, B cells, IgA, Retinoic acid, CD8+ T cells, TLR3 and Poly(I:C)
Original languageEnglish
QualificationDoctor
Awarding Institution
Supervisors/Assistant supervisor
Award date2021 Apr 13
Place of PublicationLund
Publisher
  • Lund University, Faculty of Medicine
Print ISBNs978-91-8021-032-4
Publication statusPublished - 2021
Publication categoryResearch

Bibliographic note

Defence details Date: 2021-04-13 Time: 09:00 Place: Segerfalksalen, BMC A10, Sölvegatan 17 i Lund. Join by Zoom: https://lu-se.zoom.us/j/65413960048 External reviewer(s) Name: Villablanca, Eduardo Title: docent Affiliation: Stockholm

Total downloads

No data available

Related research output

J Nakawesi, S This, J Hütter, M Boucard-Jourdin, V Barateau, K Getachew Muleta, L J Gooday, K Fog Thomsen, A Garcias López, I Ulmert, D Poncet, B Malissen, H Greenberg, O Thaunat, T Defrance, H Paidassi & K Lahl, 2021, In: Mucosal Immunology. 9, 2, p. 53-67

Research output: Contribution to journalArticle

Agnès Garcias López, Vasileios Bekiaris, Katarzyna Müller Luda, Julia Hütter, Isabel Ulmert, Konjit Getachew Muleta, Joy Nakawesi, Knut Kotarsky, Bernard Malissen, Meredith O'Keeffe, Bernhard Holzmann, William Agace & Katharina Lahl, 2020 Oct, In: European Journal of Immunology. 50, 10, p. 1525-1536 12 p.

Research output: Contribution to journalArticle

View all (2)