Classical CD4 T cells as the cornerstone of antimycobacterial immunity

Morgan, J. T.; Muskat, Kaylin; Tippalagama, Rashmi; Sette, Alessandro; Burel, Julie G.; Arlehamn, Cecilia S. Lindestam

doi:10.1111/imr.12963

Cited by 41 publications

(30 citation statements)

References 213 publications

(581 reference statements)

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“…Our results reaffirm the critical role of T cells, particularly CD4 T cells, in mediating antimycobacterial immunity 37 , both in the context of Mtb infection and vaccination 20,38-40 . The response at the mRNA level observed from post-BCG CD4 memory T cells was very similar to those in post-BCG PBMCs, suggesting that the majority of the BCG-induced gene expression changes observed in PBMCs are driven primarily by CD4 memory T cells upon BCG vaccination.…”

Section: Discussionsupporting

confidence: 78%

CD4+CCR6+ T cells dominate the BCG-induced transcriptional signature

Singhania

Dubelko

Kuan

et al. 2021

Preprint

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The century-old Mycobacterium bovis Bacillus Calmette-Guerin (BCG) remains the only licensed vaccine against tuberculosis (TB). Despite this, there is still a lot to learn about the immune response induced by BCG, both in terms of phenotype and specificity. Here, we investigated immune responses in adult individuals pre and 8 months post BCG vaccination. We specifically determined changes in gene expression, cell subset composition, DNA methylome, and the TCR repertoire induced in PBMCs and CD4 memory T cells associated with antigen stimulation by either BCG or a Mycobacterium tuberculosis (Mtb)-derived peptide pool. Following BCG vaccination, we observed increased frequencies of CCR6+ CD4 T cells, which includes both Th1* and Th17 subsets, and mucosal associated invariant T cells (MAITs). A large number of immune response genes and pathways were upregulated post BCG vaccination with similar patterns observed in both PBMCs and memory CD4 T cells, thus suggesting a substantial role for CD4 T cells in the cellular response to BCG. These upregulated genes and associated pathways were also reflected in the DNA methylome. We described both qualitative and quantitative changes in the BCG-specific TCR repertoire post vaccination, and importantly found evidence for similar TCR repertoires across different subjects. The immune signatures defined herein can be used to track and further characterize immune responses induced by BCG, and can serve as reference for benchmarking novel vaccination strategies.

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Section: Discussionsupporting

confidence: 78%

CD4+CCR6+ T cells dominate the BCG-induced transcriptional signature

Singhania

Dubelko

Kuan

et al. 2021

Preprint

Self Cite

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“…Our results reaffirm the critical role of T cells, particularly CD4 T cells, in mediating antimycobacterial immunity [57] , both in the context of Mtb infection and vaccination [ 20 , [58] , [59] , [60] ]. The response at the mRNA level observed from post-BCG CD4 memory T cells was very similar to those in post-BCG PBMCs, suggesting that the majority of the BCG-induced gene expression changes observed in PBMCs are driven primarily by CD4 memory T cells upon BCG vaccination.…”

Section: Discussionsupporting

confidence: 78%

CD4+CCR6+ T cells dominate the BCG-induced transcriptional signature

et al. 2021

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Background The century-old Mycobacterium bovis Bacillus Calmette-Guerin (BCG) remains the only licensed vaccine against tuberculosis (TB). Despite this, there is still a lot to learn about the immune response induced by BCG, both in terms of phenotype and specificity. Methods We investigated immune responses in adult individuals pre and 8 months post BCG vaccination. We specifically determined changes in gene expression, cell subset composition, DNA methylome, and the TCR repertoire induced in PBMCs and CD4 memory T cells associated with antigen stimulation by either BCG or a Mycobacterium tuberculosis ( Mtb )-derived peptide pool. Findings Following BCG vaccination, we observed increased frequencies of CCR6+ CD4 T cells, which includes both Th1* (CXCR3+CCR6+) and Th17 subsets, and mucosal associated invariant T cells (MAITs). A large number of immune response genes and pathways were upregulated post BCG vaccination with similar patterns observed in both PBMCs and memory CD4 T cells, thus suggesting a substantial role for CD4 T cells in the cellular response to BCG. These upregulated genes and associated pathways were also reflected in the DNA methylome. We described both qualitative and quantitative changes in the BCG-specific TCR repertoire post vaccination, and importantly found evidence for similar TCR repertoires across different subjects. Interpretation The immune signatures defined herein can be used to track and further characterize immune responses induced by BCG, and can serve as reference for benchmarking novel vaccination strategies.

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“…As Th2-type cytokines, especially IL-5, have been implicated in the induction of vaccine-associated disease enhancement [ 34 , 35 ], it is necessary to confirm that our SARS-CoV-2 vaccine candidate does not induce adverse immunity. An antigen delivery platform, such as the one described here, which would primarily induce T cell immunity in the absence of antibody generation, might be a valuable vaccination strategy against pathogens such as Mycobacterium tuberculosis , where T cell response (especially IFN-γ production by CD4 + T cells) is the only protective response needed [ 36 ]. In addition, such a vaccine platform carrying a foreign antigen could be used in a combination or as a boost for vaccines with a negligent or absent T cell response induction.…”

Section: Discussionmentioning

confidence: 99%

Fusion Protein of Rotavirus VP6 and SARS-CoV-2 Receptor Binding Domain Induces T Cell Responses

et al. 2021

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Vaccines based on mRNA and viral vectors are currently used in the frontline to combat the ongoing pandemic caused by the novel Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). However, there is still an urgent need for alternative vaccine technologies inducing/boosting long-lasting and cross-reactive immunity in different populations. As a possible vaccine candidate, we employed the rotavirus VP6-protein platform to construct a fusion protein (FP) displaying receptor-binding domain (RBD) of SARS-CoV-2 spike protein (S) at the N-terminus of VP6. The recombinant baculovirus-insect cell produced VP6-RBD FP was proven antigenic in vitro and bound to the human angiotensin-converting enzyme 2 (hACE2) receptor. The FP was used to immunize BALB/c mice, and humoral- and T cell-mediated immune responses were investigated. SARS-CoV-2 RBD-specific T cells were induced at a high quantity; however, no RBD or S-specific antibodies were detected. The results suggest that conformational B cell epitopes might be buried inside the VP6, while RBD-specific T cell epitopes are available for T cell recognition after the processing and presentation of FP by the antigen-presenting cells. Further immunogenicity studies are needed to confirm these findings and to assess whether, under different experimental conditions, the VP6 platform may present SARS-CoV-2 antigens to B cells as well.

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Classical CD4 T cells as the cornerstone of antimycobacterial immunity

Cited by 41 publications

References 213 publications

CD4+CCR6+ T cells dominate the BCG-induced transcriptional signature

CD4+CCR6+ T cells dominate the BCG-induced transcriptional signature

CD4+CCR6+ T cells dominate the BCG-induced transcriptional signature

Fusion Protein of Rotavirus VP6 and SARS-CoV-2 Receptor Binding Domain Induces T Cell Responses

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