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KLRG1⁺ Effector CD8⁺ T Cells Lose KLRG1, Differentiate into All Memory T Cell Lineages, and Convey Enhanced Protective Immunity.

ABSTRACT: Protective immunity against pathogens depends on the efficient generation of functionally diverse effector and memory T lymphocytes. However, whether plasticity during effector-to-memory CD8⁺ T cell differentiation affects memory lineage specification and functional versatility remains unclear. Using genetic fate mapping analysis of highly cytotoxic KLRG1⁺ effector CD8⁺ T cells, we demonstrated that KLRG1⁺ cells receiving intermediate amounts of activating and inflammatory signals downregulated KLRG1 during the contraction phase in a Bach2-dependent manner and differentiated into all memory T cell linages, including CX₃CR1^int peripheral memory cells and tissue-resident memory cells. "ExKLRG1" memory cells retained high cytotoxic and proliferative capacity distinct from other populations, which contributed to effective anti-influenza and anti-tumor immunity. Our work demonstrates that developmental plasticity of KLRG1⁺ effector CD8⁺ T cells is important in promoting functionally versatile memory cells and long-term protective immunity.

SUBMITTER: Herndler-Brandstetter D

PROVIDER: S-EPMC6465538 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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KLRG1+ Effector CD8+ T Cells Lose KLRG1, Differentiate into All Memory T Cell Lineages, and Convey Enhanced Protective Immunity.

Herndler-Brandstetter Dietmar D Ishigame Harumichi H Shinnakasu Ryo R Plajer Valerie V Stecher Carmen C Zhao Jun J Lietzenmayer Melanie M Kroehling Lina L Takumi Akiko A Kometani Kohei K Inoue Takeshi T Kluger Yuval Y Kaech Susan M SM Kurosaki Tomohiro T Okada Takaharu T Flavell Richard A RA

Immunity 20180403 4

Protective immunity against pathogens depends on the efficient generation of functionally diverse effector and memory T lymphocytes. However, whether plasticity during effector-to-memory CD8+ T cell differentiation affects memory lineage specification and functional versatility remains unclear. Using genetic fate mapping analysis of highly cytotoxic KLRG1+ effector CD8+ T cells, we demonstrated that KLRG1+ cells receiving intermediate amounts of activa ...[more]

PMID: 29625895

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Project description:IntroductionCytomegalovirus (CMV) viremia remains a major contributor to clinical complications in solid organ transplant (SOT) patients, including organ injury, morbidity and mortality. Given their critical role in antiviral defense, CD8+ T cells are essential for protective immunity against CMV.MethodsUsing single-cell RNA sequencing, we investigated the transcriptional signatures and developmental lineages of CD8+ T cells in eight immunosuppressed kidney transplant recipients (KTRs) who received organs from CMV-seropositive donors. Results were validated in a cohort of 62 KTRs using immunophenotyping.ResultsOur data revealed a significant influence of CMV serostatus on transcriptional variance of CD8+ memory T cells, associating with the first principal component from a global analysis of CD8+ T cells (p =0.0406), forming a continuum with five principal differentiation trajectories driven by CMV primary infection or reactivation. Following CMV primary infection, CD8+ T cells were hallmarked by restrained effector-memory differentiation. CD8+ T cells during CMV reactivation diverged non-linearly into senescent-like cells with signatures of arrested cell cycle, diminished translational activity and downregulated ZNF683 and longitudinally expanding effector cells with robust cytotoxic potential and upregulated ZNF683, acting as a reservoir for long-lived effector cells supporting long-term protection. Notably, CD28lo KLRG1hi IL-7R (CD127)lo HLA-DRhi CD8+ T cells present prior to the detection of viremia in CMV-seropositive patients emerged as a key feature distinguishing patients who did or did not undergo CMV reactivation after prophylaxis discontinuation (p =0.0163). Frequencies of these cells were also positively correlated with CMV-stimulated secretion of IFN-γ (p =0.0494), TNF-α (p =0.0358), MIP-1α (p =0.0262), MIP-1β (p =0.0043).DiscussionThese results provide insights into the transcriptional regulation that influences the generation of CD8+ T cell immunity to CMV and may inform strategics for monitoring host immune response to CMV to better identify and introduce therapeutic intervention to patients at risk of developing clinically significant CMV viremia.

Dataset Information

KLRG1⁺ Effector CD8⁺ T Cells Lose KLRG1, Differentiate into All Memory T Cell Lineages, and Convey Enhanced Protective Immunity.

Publications

KLRG1<sup>+</sup> Effector CD8<sup>+</sup> T Cells Lose KLRG1, Differentiate into All Memory T Cell Lineages, and Convey Enhanced Protective Immunity.

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