Plasmodium berghei Hsp90 contains a natural immunogenic I-Ab-restricted antigen common to rodent and human Plasmodium species

Enders, Matthias H.; Bayarsaikhan, Ganchimeg; Ghilas, Sonia; Chua, Yu Cheng; May, Rose; Menezes, Melody; Ge, Zhengyu; Tan, Peter; Cozijnsen, Anton; Mollard, Vanessa; Yui, Katsuyuki; McFadden, Geoffrey I.; Lahoud, Mireille H.; Caminschi, Irina; Purcell, Anthony W.; Schittenhelm, Ralf B.; Beattie, Lynette; Heath, William R.; Fernandez‐Ruiz, Daniel

doi:10.1016/j.crimmu.2021.06.002

Cited by 12 publications

(11 citation statements)

References 80 publications

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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 -/- mice (Jin et al, 2011) were kindly provided by Rachel Kuns (QIMR Berghofer Medical Research Institute). Transgenic PbTII mice (Enders et al, 2021; Fernandez-Ruiz et al, 2017) were crossed to B6. Ptprca (CD45.1 + ) mice to generate PbTII × B6.…”

Section: Methodsmentioning

confidence: 99%

“…B6.Sting -/mice (Jin et al, 2011) were kindly provided by Rachel Kuns (QIMR Berghofer Medical Research Institute). Transgenic PbTII mice (Enders et al, 2021;Fernandez-Ruiz et al, 2017) were crossed to B6.Ptprca (CD45.1 + ) mice to generate PbTII × B6.Cd45.1 (PbTII WT ; CD45.1 + CD45.2 + ). B6.Sting -/mice were crossed with PbTII mice to generate Stingdeficient PbTII mice (PbTII Sting ; CD45.1 -CD45.2 + ).…”

Section: Nucleofectionmentioning

confidence: 99%

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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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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Nucleofectionmentioning

confidence: 99%

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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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“…Previously, we used scRNA-seq to map differentiation of TCR-transgenic CD4 + T cells, termed PbTII cells (with specificity for a single epitope in Plasmodium Heat Shock Protein 90), during experimental malaria in mice [7, 15, 33]. Single naïve PbTII cells differentiated into Th1 and Tfh-like states during the first week of infection, with cellular depletion studies implicating CXCL9/10 + monocytes and B cells in controlling Th1/Tfh fate bifurcation.…”

Section: Introductionmentioning

confidence: 99%

Spatial transcriptomics maps molecular and cellular requirements for CD4⁺T cell-dependent immunity to malaria

Williams

Moreira

Asatsuma

et al. 2023

Preprint

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CD4+T cells orchestrate adaptive immunity to circulating malaria parasites; yet cellular interactions and molecular mechanisms controlling Th1 and Tfh differentiation in the spleen remain be fully defined in vivo. Here, using a murine model of CD4-dependent immunity, we tested ifSlide-seqV2, a spatial transcriptomic method with near single-cell resolution, could determine the locations of multiple CD4+T cell subsets and potentially interacting cellular partners within the spleen during infection. Firstly,Slide-seqV2readily mapped splenic cellular structure and microanatomical change during infection. Next, computational integration with scRNA-seq reference datasets of splenocytes, stromal cells, and specifically of polyclonal CD4+T cells and B cells, mapped the relative locations of multiple cell-types within this dense tissue. scRNA-seq of B cells over time mapped emergence of germinal centre B cells, red-pulp located plasmablasts and atypical B cells, and uncovered a prolonged CD4+T-cell-independent, follicular bystander B cell response, marked by Sca-1 and Ly6C upregulation. scRNA-seq of activated, polyclonal CD4+T cells revealed their similarity to our previous TCR transgenic models. Importantly, spatial analysis revealed polyclonal Th1 cells co-localised with CXCL9/10-producing monocytes in the red pulp, while polyclonal Tfh-like cells were located close to CXCL13-expressing B cell follicles, consistent with our previous CXCR3/CXCR5 competition model of Th1/Tfh bifurcation. CRISPR/Cas9 disruption of either or both CXCR3 and CXCR5 in naivePlasmodium-specific CD4+T cells had unexpectedly minor effects on Th1 differentiation in vivo. Instead, CXCR5 was essential for maximising clonal expansion, suggesting a role for splenic CXCL13+cells in supporting CD4+T cell proliferation in malaria. Thus, spatial transcriptomics at near single-cell resolution was feasible in densely packed secondary lymphoid tissue, providing multiple insights into mechanisms controlling splenic polyclonal CD4+T cell and B cell differentiation during infection.

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“…Previously, we employed TCR-transgenic (PbTII) CD4 + T cells, specific for an epitope from Plasmodium Heat Shock Protein 90 10, 11 , to map the transcriptional dynamics that underlie clonal expansion, Th1/Tfh effector fate choice 12, 13 , and transit to memory or exhausted states in experimental primary malaria 14 . These studies suggested roles for inflammatory monocytes and B cells, and the genes Tcf7 and Lgals1 in controlling T helper 1 (Th1)/T follicular helper (Tfh) fate choice, as well as revealing that memory emerges gradually over a 3-4 week period from effector counterparts.…”

Section: Introductionmentioning

confidence: 99%

CD4⁺T cells display a spectrum of recall dynamics during re-infection with malaria parasites

Lee

Moreira

et al. 2023

Preprint

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Children in malaria-endemic regions can experience multiplePlasmodiuminfections over a short period of time, within vitroCD4+T cell recall responses becoming more regulatory with increasing age and exposure. This suggests that repeated infection qualitatively changes CD4+T cells, although the heterogeneity and dynamics of these responses await systematic analysisin vivo. Here, we examined TCR transgenic PbTII and polyclonal CD4+T cells duringPlasmodiumre-infection in mice, in conjunction with scRNA-seq/TCR-seq and spatial transcriptomics at near single-cell resolution. PbTII cells gave rise to multiple antigen-experienced states in different areas of the spleen after primary infection and antimalarial treatment, including ongoing GC responses and T-cell zone memory. Upon re-infection, Th1-memory PbTII cells initiated a rapid effector response prior to proliferating, while GC Tfh cells of the same antigen specificity were entirely refractory within the same organ. Transcriptome dynamic modelling and network analysis of Th1 recall revealed a biphasic wave of RNA processing that firstly preceded immune effector transcription, and later accompanied cellular proliferation. Importantly, Th1 recall constituted a partial facsimile of primary Th1 responses, with no unique genes amongst the small subset of those upregulated upon re-infection. Finally, we noted a similar spectrum of antigen-experienced states and recall dynamics by polyclonal CD4+T cells with diverse TCRs. Therefore, during re-infection withPlasmodium, persisting GC Tfh cells remained unaltered transcriptionally, Tcm/Tfh-like cells exhibited minimal proliferation, and Th1-memory cells displayed a rapid, proliferating IL-10-producing Tr1 response consistent with a shift towards immune-regulation. These data highlight a broad spectrum of simultaneous CD4+T cell responses that occur in the spleen during re-infection with malaria parasites.HighlightsSplenic TCR transgenic CD4+T cells are highly heterogeneous prior to re-infection.Persisting GC Tfh cells are refractory to re-activation during re-infection.Th1-memory cells rapidly upregulate RNA processing prior to effector function and proliferation.Th1-recall is an imperfect but faithful facsimile of primary Th1 responses.A spectrum of recall states is observed in polyclonal CD4+T cells with diverse TCRs.

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Plasmodium berghei Hsp90 contains a natural immunogenic I-Ab-restricted antigen common to rodent and human Plasmodium species

Cited by 12 publications

References 80 publications

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

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

Spatial transcriptomics maps molecular and cellular requirements for CD4⁺T cell-dependent immunity to malaria

CD4⁺T cells display a spectrum of recall dynamics during re-infection with malaria parasites

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Plasmodium berghei Hsp90 contains a natural immunogenic I-Ab-restricted antigen common to rodent and human Plasmodium species

Cited by 12 publications

References 80 publications

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

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

Spatial transcriptomics maps molecular and cellular requirements for CD4+T cell-dependent immunity to malaria

CD4+T cells display a spectrum of recall dynamics during re-infection with malaria parasites

Contact Info

Product

Resources

About

Spatial transcriptomics maps molecular and cellular requirements for CD4⁺T cell-dependent immunity to malaria

CD4⁺T cells display a spectrum of recall dynamics during re-infection with malaria parasites