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Antigen-specific CD8 T cells in cell cycle circulate in the blood after vaccination.

ABSTRACT: Although clonal expansion is a hallmark of adaptive immunity, the location(s) where antigen-responding T cells enter cell cycle and complete it have been poorly explored. This lack of knowledge stems partially from the limited experimental approaches available. By using Ki67 plus DNA staining and a novel strategy for flow cytometry analysis, we distinguished antigen-specific CD8 T cells in G₀ , in G₁ and in S-G₂ /M phases of cell cycle after intramuscular vaccination of BALB/c mice with antigen-expressing viral vectors. Antigen-specific cells in S-G₂ /M were present at early times after vaccination in lymph nodes (LNs), spleen and, surprisingly, also in the blood, which is an unexpected site for cycling of normal non-leukaemic cells. Most proliferating cells had high scatter profile and were undetected by current criteria of analysis, which under-estimated up to 6 times antigen-specific cell frequency in LNs. Our discovery of cycling antigen-specific CD8 T cells in the blood opens promising translational perspectives.

SUBMITTER: Simonetti S

PROVIDER: S-EPMC6850756 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Antigen-specific CD8 T cells in cell cycle circulate in the blood after vaccination.

Simonetti Sonia S Natalini Ambra A Folgori Antonella A Capone Stefania S Nicosia Alfredo A Santoni Angela A Di Rosa Francesca F

Scandinavian journal of immunology 20190115 2

Although clonal expansion is a hallmark of adaptive immunity, the location(s) where antigen-responding T cells enter cell cycle and complete it have been poorly explored. This lack of knowledge stems partially from the limited experimental approaches available. By using Ki67 plus DNA staining and a novel strategy for flow cytometry analysis, we distinguished antigen-specific CD8 T cells in G0 , in G1 and in S-G2 /M phases of cell cycle after intramuscular vaccina ...[more]

PMID: 30488973

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Project description:CD8 T-cell response efficiency critically depends on the TCR binding strength to peptide-MHC, i.e., the TCR binding avidity. A current challenge in onco-immunology lies in the evaluation of vaccine protocols selecting for tumor-specific T-cells of highest avidity, offering maximal immune protection against tumor cells and clinical benefit. Here, we investigated the impact of peptide and CpG/adjuvant doses on the quality of vaccine-induced CD8 T-cells in relation to binding avidity and functional responses in treated melanoma patients. Using TCR-pMHC binding avidity measurements combined to phenotype and functional assays, we performed a comprehensive study on representative tumor antigen-specific CD8 T-cell clones (n = 454) from seven patients vaccinated with different doses of Melan-A/ELA peptide (0.1 mg vs. 0.5 mg) and CpG-B adjuvant (1-1.3 mg vs. 2.6 mg). Vaccination with high peptide dose favored the early and strong in vivo expansion and differentiation of Melan-A-specific CD8 T-cells. Consistently, T-cell clones generated from those patients showed increased TCR binding avidity (i.e., slow off-rates and CD8 binding independency) readily after 4 monthly vaccine injections (4v). In contrast, the use of low peptide or high CpG-B doses required 8 monthly vaccine injections (8v) for the enrichment of anti-tumor T-cells with high TCR binding avidity and low CD8 binding dependency. Importantly, the CD8 binding-independent vaccine-induced CD8 T-cells displayed enhanced functional avidity, reaching a plateau of maximal function. Thus, T-cell functional potency following peptide/CpG/IFA vaccination may not be further improved beyond a certain TCR binding avidity limit. Our results also indicate that while high peptide dose vaccination induced the early selection of Melan-A-specific CD8 T-cells of increased functional competence, continued serial vaccinations also promoted such high-avidity T-cells. Overall, the systematic assessment of T-cell binding avidity may contribute to optimize vaccine design for improving clinical efficacy.

Dataset Information

Antigen-specific CD8 T cells in cell cycle circulate in the blood after vaccination.

Publications

Antigen-specific CD8 T cells in cell cycle circulate in the blood after vaccination.

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