Development of a Novel CD4<sup>+</sup>TCR Transgenic Line that Reveals a Dominant Role for CD8<sup>+</sup>DC and CD40-Signaling in the Generation of Helper and CTL Responses to Blood Stage Malaria

Fernandez‐Ruiz, Daniel; Lau, Lei Shong; Ghazanfari, Nazanin; Ng, Wei Yi; Davey, Gayle M.; Berthold, Dorothée L.; Holz, Lauren E.; Kato, Yu; Bayarsaikhan, Ganchimeg; Hendriks, Sanne H.; James, Kylie R.; Cozijnsen, Anton; Mollard, Vanessa; Koning-Ward, Tania F de; Gilson, Paul R.; Kaisho, Tsuneyasu; Haque, Ashraful; Crabb, Brendan S.; Carbone, Francis R.; McFadden, Geoffrey I.; Heath, William R.

doi:10.1101/113837

Cited by 5 publications

(10 citation statements)

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“…A second substantial finding is that during severe malaria, cDC1 are critical for priming and promoting parasite‐specific Th1 CD4 T cells. This is consistent with the results of a study using a CD4 TCR‐transgenic mouse specific for a Plasmodium epitope (Fernandez‐Ruiz et al , ). More generally, these data are in line with the established propensity of cDC1 to secrete IL‐12 during infection by intracellular pathogens (Mashayekhi et al , ; Alexandre et al , ) and the implication of cDC1 in Th1 polarization during other parasitic infections such as leishmaniasis (Ashok et al , ; Martinez‐Lopez et al , ) and toxoplasmosis (Mashayekhi et al , ).…”

Section: Discussionsupporting

confidence: 92%

“…However, our finding that cDC1 from naïve mice also present pRBC‐derived antigens better than cDC2 suggests that this difference is not, or at least not solely, dictated by infection. Using a CD4 T‐cell hybridoma that recognizes a currently undefined Plasmodium epitope, a Biorxiv‐posted study (Fernandez‐Ruiz et al , ) reports that cDC1 are more stimulatory than CD4 + DC and double‐negative DC, both in naïve mice and at 3 days post‐infection. Although the sensitivity of our hybridomas did not allow us to evaluate the ETRAMP10.2 MHC II presentation at such an early time point (data not shown), our data are consistent with this work.…”

Section: Discussionmentioning

confidence: 99%

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Profiling MHC II immunopeptidome of blood‐stage malaria reveals that cDC 1 control the functionality of parasite‐specific CD 4 T cells

et al. 2017

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In malaria, CD4 Th1 and T follicular helper (TFH) cells are important for controlling parasite growth, but Th1 cells also contribute to immunopathology. Moreover, various regulatory CD4 T‐cell subsets are critical to hamper pathology. Yet the antigen‐presenting cells controlling Th functionality, as well as the antigens recognized by CD4 T cells, are largely unknown. Here, we characterize the MHC II immunopeptidome presented by DC during blood‐stage malaria in mice. We establish the immunodominance hierarchy of 14 MHC II ligands derived from conserved parasite proteins. Immunodominance is shaped differently whether blood stage is preceded or not by liver stage, but the same ETRAMP‐specific dominant response develops in both contexts. In naïve mice and at the onset of cerebral malaria, CD8α+ dendritic cells (cDC1) are superior to other DC subsets for MHC II presentation of the ETRAMP epitope. Using in vivo depletion of cDC1, we show that cDC1 promote parasite‐specific Th1 cells and inhibit the development of IL‐10+ CD4 T cells. This work profiles the P. berghei blood‐stage MHC II immunopeptidome, highlights the potency of cDC1 to present malaria antigens on MHC II, and reveals a major role for cDC1 in regulating malaria‐specific CD4 T‐cell responses.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Profiling MHC II immunopeptidome of blood‐stage malaria reveals that cDC 1 control the functionality of parasite‐specific CD 4 T cells

et al. 2017

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“…Overall, our findings are remarkably similar to the phenotype of IL-12p40 KO mice described by Stevenson and Su nearly a decade ago [289]. A very recent study utilizing the newly created Pb-TII CD4 transgenic T-cell line and XCR-1-DTR transgenic mouse model recapitulated similar findings and roles of CD8 + DCs in CD4 + and CD8 + T-cell priming in the PbA ECM model [438].…”

Section: Discussionsupporting

confidence: 89%

Modulation of adaptive and innate immune responses by myeloid cells during malaria

Lai¹

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Plasmodium chabaudi chabaudi AS infection 4.2.1. Absence of Clec9A + DCs dysregulates induction of Th1 proinflammatory responses and T effector polyfunctionality in PccAS infection 4.2.2. An intact innate immune compartment compensates for polyfunctional proinflammatory responses in the absence of Clec9A + DCs 4.2.3. Germinal center reactions, B-cell responses and Ig production are not abrogated in absence of Clec9A + DCs 4.2.4. Absence of Clec9A + DCs diminishes Th1-like effector TFH and proinflammatory signals required for class switch recombination to more protective Th1 IgG2 and IgG3 4.2.5. The Th1-TFH relationship conundrum 4.2.6. Clec9A + DC deficiency results in persistent T effector and memory precursor impairment during recrudescent PccAS infection 4.3. Caveats and limitations in the Clec9A-DTR PccAS infection model 4.4. Organ-specific tissue-resident macrophages are replenished with different kinetics during acute Plasmodium yoelii infection 4.4.1. Emptied embryonically-seeded TRMØ niches in spleen and liver are partially replenished by BM-derived monocytic progenitors that differentiate into stable, bona fide TRMØs 4.4.2. Depleted lung alveolar MØs almost exclusively self-renew 8 with negligible input from BM-derived circulatory monocytes during acute Py1.1GFP infection 4.5. Rapidly-responding Ly6C hi inflammatory monocytes and monocyte-derived MØs massively infiltrate afflicted tissues and contribute to Py1.1GFP clearance 4.5.1. Ly6C hi inflammatory monocytes rapidly and massively infiltrate organs upon Py1.1GFP infection 4.5.2. Concerted efforts of FrII inflammatory monocytes and monocyte-derived / other tissue-resident MØs in resolution of Py1.1GFP infection 4.6. BM monocyte-derived MØs are phenotypically and transcriptionally similar to bona fide embryonic tissue-resident MØs 4.7. Plasmodium infection as a new precedent for the general mechanism of beneficial cell suicide 5. Summary 6. Significance of studies on current malaria immunological research 6.1. Clec9A + DCs and their roles in anti-Plasmodium immunity 6.2. Tissue-resident MØ repopulation kinetics during Plasmodium infection 6.3. Concluding remarks 7. Appendix 7.1. Cell phenotype profile 7.2. List of antibody panels 7.3. Supplementary figures 8. References 9. Author's publication(s) 10. Oral and poster presentations 9 Abbreviations ACT Artemisinin-based combination therapy ADCI Antibody-dependent cellular inhibition APC Antigen presenting cells AGM Aorta-gonad-mesonephros AMØ Alveolar macrophage Baf8 Basic leucine zipper ATF-like transcription factor BBB Blood-brain barrier BM Bone marrow BMEM Memory B-cells CD Cluster of differentiation cDC Conventional dendritic cells cKit Tyrosine-protein kinase Kit CSF-1/MCF-1 Colony stimulating factor 1 CCL CC motif chemokine ligand CCR CC chemokine receptor CDP Common dendritic progenitor CLEC9A C-type lectin receptor 9A CMP Common myeloid progenitor CMoP Common monocyte progenitor CTL Cytotoxic T lymphocytes CX3CR1 CX3C chemokine receptor 1 CXCR5 C-X-C chemokine receptor type 5 DNA Deoxyribonucleic ...

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“…To extend the above studies to an in vivo setting, we used an experimental model of severe malaria caused by infection of C57BL/6 mice with P. berghei ANKA ( Pb A). We employed PbTII mice (Enders et al, 2021; Fernandez-Ruiz et al, 2017), a TCR transgenic mouse line that produce CD4 + T cells specific for I-A b -restricted PbA heat shock protein 90 expressed by all rodent and human Plasmodium species, and crossed these with Tmem173 -deficient mice (James et al, 2018; Jin et al, 2011) to generate STING-deficient PbTII cells (PbTII ΔSting ). Wild-type control PbTII cells were generated by crossing PbTII TCR transgenic mice with congenic (CD45.1) C57BL/6 mice to produce mice expressing both cd45.1 and cd45.2 alleles (PbTII WT ).…”

Section: Resultsmentioning

confidence: 99%

STING activation promotes autologous type I interferon-dependent development of type 1 regulatory T cells during malaria

Wang

Rivera

Edwards

et al. 2022

Preprint

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The development of highly effective malaria vaccines and improving drug treatment protocols to boost anti-parasitic immunity is critical for malaria elimination. However, these efforts are hampered by parasite-specific immunoregulatory networks that are rapidly established following exposure to malaria parasites. Here, we identify stimulator of interferon genes (STING) as a critical mediator of type I interferon production by CD4+ T cells during blood-stage Plasmodium falciparum infection. STING activation by cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) stimulated IFNB gene transcription that promoted development of IL-10 and IFNγ co-producing CD4+ T (type I regulatory; Tr1) cells. CD4+ T cell sensitivity to STING phosphorylation increased in healthy volunteers following P. falciparum infection, particularly in Tr1 cells. Finally, we found the JAK1/2 inhibitor ruxolitinib modulated this innate signalling axis in CD4+ T cells to increase parasite-specific Th1 and diminish Tr1 cell responses. These findings identify STING as a critical mediator of Tr1 cell development during malaria.

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

Cited by 5 publications

References 83 publications

Profiling MHC II immunopeptidome of blood‐stage malaria reveals that cDC 1 control the functionality of parasite‐specific CD 4 T cells

Profiling MHC II immunopeptidome of blood‐stage malaria reveals that cDC 1 control the functionality of parasite‐specific CD 4 T cells

Modulation of adaptive and innate immune responses by myeloid cells during malaria

STING activation promotes autologous type I interferon-dependent development of type 1 regulatory T cells during malaria

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

Cited by 5 publications

References 83 publications

Profiling MHC II immunopeptidome of blood‐stage malaria reveals that cDC 1 control the functionality of parasite‐specific CD 4 T cells

Profiling MHC II immunopeptidome of blood‐stage malaria reveals that cDC 1 control the functionality of parasite‐specific CD 4 T cells

Modulation of adaptive and innate immune responses by myeloid cells during malaria

STING activation promotes autologous type I interferon-dependent development of type 1 regulatory T cells during malaria

Contact Info

Product

Resources

About

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