Development of a Novel CD4 + TCR Transgenic Line That Reveals a Dominant Role for CD8 + Dendritic Cells and CD40 Signaling in the Generation of Helper and CTL Responses to Blood-Stage Malaria

We describe an MHC class II (I-A )-restricted TCR transgenic mouse line that produces CD4 T cells specific for species. This line, termed PbT-II, was derived from a CD4 T cell hybridoma generated to blood-stage ANKA (PbA). PbT-II cells responded to all species and stages tested so far, including rod...

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Published inThe Journal of immunology (1950) Vol. 199; no. 12; pp. 4165 - 4179
Main Authors Fernandez-Ruiz, Daniel, Lau, Lei Shong, Ghazanfari, Nazanin, Jones, Claerwen M, Ng, Wei Yi, Davey, Gayle M, Berthold, Dorothee, Holz, Lauren, Kato, Yu, Enders, Matthias H, Bayarsaikhan, Ganchimeg, Hendriks, Sanne H, Lansink, Lianne I M, Engel, Jessica A, Soon, Megan S F, James, Kylie R, Cozijnsen, Anton, Mollard, Vanessa, Uboldi, Alessandro D, Tonkin, Christopher J, de Koning-Ward, Tania F, Gilson, Paul R, Kaisho, Tsuneyasu, Haque, Ashraful, Crabb, Brendan S, Carbone, Francis R, McFadden, Geoffrey I, Heath, William R
Format Journal Article
LanguageEnglish
Published United States American Association of Immunologists 15.12.2017
AAI
Subjects
Antigen presentation
Antigen-presenting cells
Blood
CD4 antigen
CD40 antigen
CD40L protein
CD8 antigen
Cell activation
Cytotoxicity
Dendritic cells
Depletion
Extracellular matrix
Infections
Lymphocytes
Lymphocytes T
Major histocompatibility complex
Malaria
Novel Immunological Methods
Parasites
Plasmodium
Polybutylene terephthalates
Rodents
Sporozoites
T cell receptors
Transgenic mice
Vector-borne diseases
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Abstract We describe an MHC class II (I-A )-restricted TCR transgenic mouse line that produces CD4 T cells specific for species. This line, termed PbT-II, was derived from a CD4 T cell hybridoma generated to blood-stage ANKA (PbA). PbT-II cells responded to all species and stages tested so far, including rodent (PbA, NK65, AS, and 17XNL) and human ( ) blood-stage parasites as well as irradiated PbA sporozoites. PbT-II cells can provide help for generation of Ab to infection and can control this otherwise lethal infection in CD40L-deficient mice. PbT-II cells can also provide help for development of CD8 T cell-mediated experimental cerebral malaria (ECM) during PbA infection. Using PbT-II CD4 T cells and the previously described PbT-I CD8 T cells, we determined the dendritic cell (DC) subsets responsible for immunity to PbA blood-stage infection. CD8 DC (a subset of XCR1 DC) were the major APC responsible for activation of both T cell subsets, although other DC also contributed to CD4 T cell responses. Depletion of CD8 DC at the beginning of infection prevented ECM development and impaired both Th1 and follicular Th cell responses; in contrast, late depletion did not affect ECM. This study describes a novel and versatile tool for examining CD4 T cell immunity during malaria and provides evidence that CD4 T cell help, acting via CD40L signaling, can promote immunity or pathology to blood-stage malaria largely through Ag presentation by CD8 DC.
AbstractList We describe an MHC class II (I-Ab)–restricted TCR transgenic mouse line that produces CD4+ T cells specific for Plasmodium species. This line, termed PbT-II, was derived from a CD4+ T cell hybridoma generated to blood-stage Plasmodium berghei ANKA (PbA). PbT-II cells responded to all Plasmodium species and stages tested so far, including rodent (PbA, P. berghei NK65, Plasmodium chabaudi AS, and Plasmodium yoelii 17XNL) and human (Plasmodium falciparum) blood-stage parasites as well as irradiated PbA sporozoites. PbT-II cells can provide help for generation of Ab to P. chabaudi infection and can control this otherwise lethal infection in CD40L-deficient mice. PbT-II cells can also provide help for development of CD8+ T cell–mediated experimental cerebral malaria (ECM) during PbA infection. Using PbT-II CD4+ T cells and the previously described PbT-I CD8+ T cells, we determined the dendritic cell (DC) subsets responsible for immunity to PbA blood-stage infection. CD8+ DC (a subset of XCR1+ DC) were the major APC responsible for activation of both T cell subsets, although other DC also contributed to CD4+ T cell responses. Depletion of CD8+ DC at the beginning of infection prevented ECM development and impaired both Th1 and follicular Th cell responses; in contrast, late depletion did not affect ECM. This study describes a novel and versatile tool for examining CD4+ T cell immunity during malaria and provides evidence that CD4+ T cell help, acting via CD40L signaling, can promote immunity or pathology to blood-stage malaria largely through Ag presentation by CD8+ DC.
We describe an MHC class II (I-A b )–restricted TCR transgenic mouse line that produces CD4 + T cells specific for Plasmodium species. This line, termed PbT-II, was derived from a CD4 + T cell hybridoma generated to blood-stage Plasmodium berghei ANKA (PbA). PbT-II cells responded to all Plasmodium species and stages tested so far, including rodent (PbA, P. berghei NK65, Plasmodium chabaudi AS, and Plasmodium yoelii 17XNL) and human ( Plasmodium falciparum ) blood-stage parasites as well as irradiated PbA sporozoites. PbT-II cells can provide help for generation of Ab to P. chabaudi infection and can control this otherwise lethal infection in CD40L-deficient mice. PbT-II cells can also provide help for development of CD8 + T cell–mediated experimental cerebral malaria (ECM) during PbA infection. Using PbT-II CD4 + T cells and the previously described PbT-I CD8 + T cells, we determined the dendritic cell (DC) subsets responsible for immunity to PbA blood-stage infection. CD8 + DC (a subset of XCR1 + DC) were the major APC responsible for activation of both T cell subsets, although other DC also contributed to CD4 + T cell responses. Depletion of CD8 + DC at the beginning of infection prevented ECM development and impaired both Th1 and follicular Th cell responses; in contrast, late depletion did not affect ECM. This study describes a novel and versatile tool for examining CD4 + T cell immunity during malaria and provides evidence that CD4 + T cell help, acting via CD40L signaling, can promote immunity or pathology to blood-stage malaria largely through Ag presentation by CD8 + DC.
We describe an MHC class II (I-A )-restricted TCR transgenic mouse line that produces CD4 T cells specific for species. This line, termed PbT-II, was derived from a CD4 T cell hybridoma generated to blood-stage ANKA (PbA). PbT-II cells responded to all species and stages tested so far, including rodent (PbA, NK65, AS, and 17XNL) and human ( ) blood-stage parasites as well as irradiated PbA sporozoites. PbT-II cells can provide help for generation of Ab to infection and can control this otherwise lethal infection in CD40L-deficient mice. PbT-II cells can also provide help for development of CD8 T cell-mediated experimental cerebral malaria (ECM) during PbA infection. Using PbT-II CD4 T cells and the previously described PbT-I CD8 T cells, we determined the dendritic cell (DC) subsets responsible for immunity to PbA blood-stage infection. CD8 DC (a subset of XCR1 DC) were the major APC responsible for activation of both T cell subsets, although other DC also contributed to CD4 T cell responses. Depletion of CD8 DC at the beginning of infection prevented ECM development and impaired both Th1 and follicular Th cell responses; in contrast, late depletion did not affect ECM. This study describes a novel and versatile tool for examining CD4 T cell immunity during malaria and provides evidence that CD4 T cell help, acting via CD40L signaling, can promote immunity or pathology to blood-stage malaria largely through Ag presentation by CD8 DC.
Author Carbone, Francis R
James, Kylie R
McFadden, Geoffrey I
Berthold, Dorothee
Gilson, Paul R
Cozijnsen, Anton
Tonkin, Christopher J
Crabb, Brendan S
Lansink, Lianne I M
Uboldi, Alessandro D
Bayarsaikhan, Ganchimeg
Ng, Wei Yi
Davey, Gayle M
Hendriks, Sanne H
Kaisho, Tsuneyasu
Ghazanfari, Nazanin
Haque, Ashraful
Engel, Jessica A
Soon, Megan S F
Enders, Matthias H
de Koning-Ward, Tania F
Mollard, Vanessa
Heath, William R
Fernandez-Ruiz, Daniel
Lau, Lei Shong
Jones, Claerwen M
Holz, Lauren
Kato, Yu
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  email: wrheath@unimelb.edu.au
  organization: Australian Research Council Centre of Excellence in Advanced Molecular Imaging, The University of Melbourne, Parkville, Victoria 3010, Australia
BackLink https://www.ncbi.nlm.nih.gov/pubmed/29084838$$D View this record in MEDLINE/PubMed
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ContentType Journal Article
Copyright Copyright © 2017 by The American Association of Immunologists, Inc.
Copyright American Association of Immunologists Dec 15, 2017
Copyright © 2017 by The American Association of Immunologists, Inc. 2017 Copyright © 2017 by The American Association of Immunologists, Inc.
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D.F.-R. designed and performed the research and wrote the manuscript; L.S.L., N.G., C.M.J., W.Y.N., G.M.D., D.B., L.H., Y.K., G.B., S.H.H., K.R.J., M.H.E., L.I.M.L., J.A.E., and M.S.F.S. performed research; A.C., V.M., T.F.d.K.-W., P.R.G., A.D.U., C.J.T., T.K., and G.I.M. provided reagents; A.H., B.S.C., and F.R.C. designed the research; W.R.H. designed the research and wrote the manuscript.
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SSID ssj0006024
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Snippet We describe an MHC class II (I-A )-restricted TCR transgenic mouse line that produces CD4 T cells specific for species. This line, termed PbT-II, was derived...
We describe an MHC class II (I-Ab)–restricted TCR transgenic mouse line that produces CD4+ T cells specific for Plasmodium species. This line, termed PbT-II,...
We describe an MHC class II (I-Ab)-restricted TCR transgenic mouse line that produces CD4+ T cells specific for Plasmodium species. This line, termed PbT-II,...
We describe an MHC class II (I-A b )–restricted TCR transgenic mouse line that produces CD4 + T cells specific for Plasmodium species. This line, termed...
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SubjectTerms Antigen presentation
Antigen-presenting cells
Blood
CD4 antigen
CD40 antigen
CD40L protein
CD8 antigen
Cell activation
Cytotoxicity
Dendritic cells
Depletion
Extracellular matrix
Infections
Lymphocytes
Lymphocytes T
Major histocompatibility complex
Malaria
Novel Immunological Methods
Parasites
Plasmodium
Polybutylene terephthalates
Rodents
Sporozoites
T cell receptors
Transgenic mice
Vector-borne diseases
Title Development of a Novel CD4 + TCR Transgenic Line That Reveals a Dominant Role for CD8 + Dendritic Cells and CD40 Signaling in the Generation of Helper and CTL Responses to Blood-Stage Malaria
URI https://www.ncbi.nlm.nih.gov/pubmed/29084838
https://www.proquest.com/docview/1983937774
https://search.proquest.com/docview/1958535115
https://pubmed.ncbi.nlm.nih.gov/PMC5713497
Volume 199
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