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Single-cell profiling of lineage determining transcription factors in antigen-specific CD4⁺ T cells reveals unexpected complexity in recall responses during immune reconstitution.

ABSTRACT: Recent studies of protein and gene expression at the single-cell level have revealed that the memory T-cell compartment is more heterogeneous than previously acknowledged. Identifying different T helper subsets involved in memory responses at the single-cell level is thus necessary to understand the level of heterogeneity within this population. Antigen-specific CD4⁺ T cells were measured using the CD25/OX40 assay together with a qualitative multiplex single-cell RT-PCR assay. Transcription profiles and subset proportions within the antigen-specific CD4⁺ T-cell population were dissected. Cytomegalovirus (CMV)-specific CD4⁺ T-cell responses skewed toward a Th1 response, whereas Tetanus toxoid responses skewed toward a Th2 type response. Fluctuations in CD4⁺ T-cell subsets were observed within the HIV-Gag-specific response during ongoing antiretroviral therapy. Strong effector responses (Th1) were observed in early treatment, however with ongoing therapy this effector response significantly decreased in combination with an increase in Tregs and circulating Tfh-like BCL-6⁺ memory cells. The apparent increase in Tcm in peripheral blood after a several weeks of antiretroviral therapy may be due to Tfh-like cell egress from germinal centers into the periphery.

SUBMITTER: Phetsouphanh C

PROVIDER: S-EPMC5550558 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Single-cell profiling of lineage determining transcription factors in antigen-specific CD4<sup>+</sup> T cells reveals unexpected complexity in recall responses during immune reconstitution.

Phetsouphanh Chansavath C Xu Yin Y Munier Mee Ling ML Zaunders John J JJ Kelleher Anthony D AD

Immunology and cell biology 20170509 7

Recent studies of protein and gene expression at the single-cell level have revealed that the memory T-cell compartment is more heterogeneous than previously acknowledged. Identifying different T helper subsets involved in memory responses at the single-cell level is thus necessary to understand the level of heterogeneity within this population. Antigen-specific CD4<sup>+</sup> T cells were measured using the CD25/OX40 assay together with a qualitative multiplex single-cell RT-PCR assay. Transcr ...[more]

PMID: 28485382

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Project description:BackgroundAntitumor mechanisms of CD4+ T cells remain crudely defined, and means to effectively harness CD4+ T-cell help for cancer immunotherapy are lacking. Pre-existing memory CD4+ T cells hold potential to be leveraged for this purpose. Moreover, the role of pre-existing immunity in virotherapy, particularly recombinant poliovirus immunotherapy where childhood polio vaccine specific immunity is ubiquitous, remains unclear. Here we tested the hypothesis that childhood vaccine-specific memory T cells mediate antitumor immunotherapy and contribute to the antitumor efficacy of polio virotherapy.MethodsThe impact of polio immunization on polio virotherapy, and the antitumor effects of polio and tetanus recall were tested in syngeneic murine melanoma and breast cancer models. CD8+ T-cell and B-cell knockout, CD4+ T-cell depletion, CD4+ T-cell adoptive transfer, CD40L blockade, assessments of antitumor T-cell immunity, and eosinophil depletion defined antitumor mechanisms of recall antigens. Pan-cancer transcriptome data sets and polio virotherapy clinical trial correlates were used to assess the relevance of these findings in humans.ResultsPrior vaccination against poliovirus substantially bolstered the antitumor efficacy of polio virotherapy in mice, and intratumor recall of poliovirus or tetanus immunity delayed tumor growth. Intratumor recall antigens augmented antitumor T-cell function, caused marked tumor infiltration of type 2 innate lymphoid cells and eosinophils, and decreased proportions of regulatory T cells (Tregs). Antitumor effects of recall antigens were mediated by CD4+ T cells, limited by B cells, independent of CD40L, and dependent on eosinophils and CD8+ T cells. An inverse relationship between eosinophil and Treg signatures was observed across The Cancer Genome Atlas (TCGA) cancer types, and eosinophil depletion prevented Treg reductions after polio recall. Pretreatment polio neutralizing antibody titers were higher in patients living longer, and eosinophil levels increased in the majority of patients, after polio virotherapy.ConclusionPre-existing anti-polio immunity contributes to the antitumor efficacy of polio virotherapy. This work defines cancer immunotherapy potential of childhood vaccines, reveals their utility to engage CD4+ T-cell help for antitumor CD8+ T cells, and implicates eosinophils as antitumor effectors of CD4+ T cells.

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Single-cell profiling of lineage determining transcription factors in antigen-specific CD4⁺ T cells reveals unexpected complexity in recall responses during immune reconstitution.

Publications

Single-cell profiling of lineage determining transcription factors in antigen-specific CD4<sup>+</sup> T cells reveals unexpected complexity in recall responses during immune reconstitution.

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OmicsDI is part of the ELIXIR infrastructure

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Single-cell profiling of lineage determining transcription factors in antigen-specific CD4+ T cells reveals unexpected complexity in recall responses during immune reconstitution.

Publications

Single-cell profiling of lineage determining transcription factors in antigen-specific CD4<sup>+</sup> T cells reveals unexpected complexity in recall responses during immune reconstitution.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Single-cell profiling of lineage determining transcription factors in antigen-specific CD4⁺ T cells reveals unexpected complexity in recall responses during immune reconstitution.