CD49d marks Th1 and Tfh-like antigen-specific CD4+ T cells during <i>Plasmodium chabaudi</i> infection

Jian, Jiun-Yu; Inoue, Shinichi; Bayarsaikhan, Ganchimeg; Miyakoda, Mana; Kimura, Daisuke; Kimura, Kazuhiro; Nozaki, Eriko; Sakurai, Takeshi; Fernandez‐Ruiz, Daniel; Heath, William R.; Yui, Katsuyuki

doi:10.1093/intimm/dxab020

Cited by 14 publications

(10 citation statements)

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“…4B), as well as capturing higher frequencies of CXCR5 + cells compared to a previous approach of examining CD11a hi CD49d + cells (Extended Data Fig. 6A-B) [41]. Splenic CD11a hi CXCR3 + CD4 + polyclonal T cells and GFP + PbTII cells were recovered 7 days p.i.…”

Section: Resultsmentioning

confidence: 77%

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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Section: Resultsmentioning

confidence: 77%

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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“…Using TCR transgenic PbTIIs, we had noted varying magnitudes and dynamics of transcriptional responses mounted by splenic antigen-experienced CD4 + T cells during re-infection. To determine the relevance of our findings to TCR diverse polyclonal CD4 + T cells, we first transferred naïve PbTIIs, infected and drug-cured mice as above, and determined if co-expression of the markers CD11a, as previously reported 25,26,27 , and CXCR3 (as suggested from our previous study 14,28 ) would permit flow-cytometric enrichment of polyclonal, activated CD4 + T cells (Figure 6A). We noted firstly, that PbTIIs prior to and 2 days after re-infection expressed high levels of CD11a and CXCR3 (Figure 6A).…”

Section: Tcr Diverse Antigen-experienced Cd4 + T Cells In the Spleen ...mentioning

confidence: 77%

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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“…It is possible that the CD8 T cell response induced following vaccination may not be entirely mCAR12 and mCDK12 specific. A recent study using a Plasmodium infection model indicated that activated CD4 T cells develop into both CD11a hi CD49d hi type 1 helper T (Th1) cells and CD11a hi CD49d lo follicular helper T (Tfh)-like cells ( 37 ). The exact mechanism through which neoantigen-specific CD4 T cells mediate tumor regression is unknown at this point.…”

Section: Discussionmentioning

confidence: 99%

“…hi CD49d hi type 1 helper T (Th1) cells and CD11a hi CD49d lo follicular helper T (Tfh)-like cells(37). The exact mechanism through which neoantigen-specific CD4 T cells mediate tumor regression is unknown at this point.…”

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confidence: 99%

Combination TIGIT/PD-1 blockade enhances the efficacy of neoantigen vaccines in a model of pancreatic cancer

et al. 2022

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BackgroundCancer neoantigens are important targets of cancer immunotherapy and neoantigen vaccines are currently in development in pancreatic ductal adenocarcinoma (PDAC) and other cancer types. Immune regulatory mechanisms in pancreatic cancer may limit the efficacy of neoantigen vaccines. Targeting immune checkpoint signaling pathways in PDAC may improve the efficacy of neoantigen vaccines.MethodsWe used KPC4580P, an established model of PDAC, to test whether neoantigen vaccines can generate therapeutic efficacy against PDAC. We focused on two immunogenic neoantigens associated with genetic alterations in the CAR12 and CDK12 genes. We tested a neoantigen vaccine comprised of two 20-mer synthetic long peptides and poly IC, a Toll-like receptor (TLR) agonist. We investigated the ability of neoantigen vaccine alone, or in combination with PD-1 and TIGIT signaling blockade to impact tumor growth. We also assessed the impact of TIGIT signaling on T cell responses in human PDAC.ResultsNeoantigen vaccines induce neoantigen-specific T cell responses in tumor-bearing mice and slow KPC4580P tumor growth. However, KPC4580P tumors express high levels of PD-L1 and the TIGIT ligand, CD155. A subset of neoantigen-specific T cells in KPC4580P tumors are dysfunctional, and express high levels of TIGIT. PD-1 and TIGIT signaling blockade in vivo reverses T cell dysfunction and enhances neoantigen vaccine-induced T cell responses and tumor regression. In human translational studies, TIGIT signaling blockade in vitro enhances neoantigen-specific T cell function following vaccination.ConclusionsTaken together, preclinical and human translational studies support testing neoantigen vaccines in combination with therapies targeting the PD-1 and TIGIT signaling pathways in patients with PDAC.

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CD49d marks Th1 and Tfh-like antigen-specific CD4+ T cells during Plasmodium chabaudi infection

Cited by 14 publications

References 44 publications

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

Combination TIGIT/PD-1 blockade enhances the efficacy of neoantigen vaccines in a model of pancreatic cancer

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CD49d marks Th1 and Tfh-like antigen-specific CD4+ T cells during Plasmodium chabaudi infection

Cited by 14 publications

References 44 publications

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

Combination TIGIT/PD-1 blockade enhances the efficacy of neoantigen vaccines in a model of pancreatic cancer

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