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Sestrins induce natural killer function in senescent-like CD8⁺ T cells.

ABSTRACT: Aging is associated with remodeling of the immune system to enable the maintenance of life-long immunity. In the CD8⁺ T cell compartment, aging results in the expansion of highly differentiated cells that exhibit characteristics of cellular senescence. Here we found that CD27^-CD28^-CD8⁺ T cells lost the signaling activity of the T cell antigen receptor (TCR) and expressed a protein complex containing the agonistic natural killer (NK) receptor NKG2D and the NK adaptor molecule DAP12, which promoted cytotoxicity against cells that expressed NKG2D ligands. Immunoprecipitation and imaging cytometry indicated that the NKG2D-DAP12 complex was associated with sestrin 2. The genetic inhibition of sestrin 2 resulted in decreased expression of NKG2D and DAP12 and restored TCR signaling in senescent-like CD27^-CD28^-CD8⁺ T cells. Therefore, during aging, sestrins induce the reprogramming of non-proliferative senescent-like CD27^-CD28^-CD8⁺ T cells to acquire a broad-spectrum, innate-like killing activity.

SUBMITTER: Pereira BI

PROVIDER: S-EPMC10249464 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Sestrins induce natural killer function in senescent-like CD8+ T cells.

Pereira Branca I BI De Maeyer Roel P H RPH Covre Luciana P LP Nehar-Belaid Djamel D Lanna Alessio A Ward Sophie S Marches Radu R Chambers Emma S ES Gomes Daniel C O DCO Riddell Natalie E NE Maini Mala K MK Teixeira Vitor H VH Janes Samuel M SM Gilroy Derek W DW Larbi Anis A Mabbott Neil A NA Ucar Duygu D Kuchel George A GA Henson Sian M SM Strid Jessica J Lee Jun H JH Banchereau Jacques J Akbar Arne N AN

Nature immunology 20200330 6

Aging is associated with remodeling of the immune system to enable the maintenance of life-long immunity. In the CD8+ T cell compartment, aging results in the expansion of highly differentiated cells that exhibit characteristics of cellular senescence. Here we found that CD27-CD28-CD8+ T cells lost the signaling activity of the T cell antigen receptor (TCR) and expressed a protein complex containing the agonistic natural killer (NK) receptor NKG2D and ...[more]

PMID: 32231301

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Project description:The antiviral response of natural killer (NK) cells and CD8+ T cells is weak in patients with chronic hepatitis B (CHB) infection. However, the specific characteristics of these cells and the association between NK cells and CD8+ T cell dysfunction is not well known. In this study, higher galectin-9 (Gal-9) expression was observed in circulating NK cells from CHB patients than from healthy controls and was found to contribute to NK cell dysfunction. In addition, circulating CD8+ T cells showed obvious dysfunction and overexpressed TIM-3, the natural receptor of Gal-9, during active CHB infection. Gal-9+ and Gal-9- NK cells from active CHB patients were sorted and cocultured with autologous CD8+ T cells. The proportion of tetramer+CD8+ T cells and the cytokines production of CD8+ T cells were lower after cocultivation with Gal-9+ than with Gal-9- NK cells. We showed that in vitro depletion of NK cells increased circulating hepatitis B virus (HBV)-specific CD8+ T cell responses in patients with active CHB infection. Because Gal-9 is increased in the serum of CHB patients, CD8+ T cells were sorted and cultured with exogenous Gal-9, resulting in lower IFN-γ, TNF-α, CD107a, and granzyme B levels, decreased expression of the activation receptor CD69, increased expression of TIM-3, and a high percentage of early apoptotic CD8+ T cells. Blocking Gal-9 or TIM-3 in vitro in a culture of peripheral blood mononuclear cells (PBMCs) stimulated with HBV peptide from active CHB patients restored CD8+ T cell function. However, blocking Gal-9 in vitro after removal of NK cells from PBMCs did not rescue CD8+ T cells exhaustion. Furthermore, NK and CD8+ T cells from active CHB patients were sorted and cocultured in vitro, and the exhaustion of CD8+ T cells were alleviated after blocking Gal-9 or TIM-3. In summary, overexpression of Gal-9 on NK cells, which interacts with TIM-3+CD8+ T cells and likely contributes to antiviral CD8+ T cell dysfunction, may be a potential target for the treatment of CHB patients.

Project description:BackgroundLiver transplantation (LT) offers a good survival chance for both the patient in short or long term, but still faces many challenges in the treatment of LT, such as the side effects associated with long-term immunosuppression, which is one of the side effects that occurs in most patients. However, the dynamics of the cellular immune system composition over time during immune tolerance to LT after immunosuppressive therapy are not known.MethodsUsing single-cell transcriptome sequencing, we analyzed five peripheral blood samples (one normal individual and four patients who underwent LT and received immunosuppressive therapy for 2 months, 1 year, 3 years, and 7 years, respectively) for immune cell composition and gene expression.ResultsA total of 17,462 peripheral blood mononuclear cells were acquired from a normal individual without LT and patients who underwent LT and received immunosuppressive therapy for 2 months, 1 year, 3 years, and 7 years, respectively. A total of 24 cell clusters were obtained and categorized into four different cell types based on gene expression characteristics as follows: eight clusters of T cells, two clusters of B cells, two clusters of neutrophils, two clusters of monocytes, natural killer cells, and natural killer T (NKT) cells (n = 4), and six other cell clusters. Cell subset analysis, pseudotime analysis, and intercellular communication analysis revealed that the CD8+ NKT cells specifically expressed NKG2A (KLRC1, CD159A), which may be an important cell group for CD8+ NKG2A+ NKT cells in LT, thereby highlighting the heterogeneity and functional diversity in patients who undergo LT.ConclusionsWe comprehensively analyzed single-cell RNA sequencing data from a normal individual and patients who underwent LT and elucidated the mechanism underlying the development of immune tolerance in LT. CD8+ NKT cells specifically expressing KLRC1 play a crucial role in LT, and dynamic monitoring of these cells may provide novel avenues for the diagnosis and treatment of LT-related immune rejection.

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Sestrins induce natural killer function in senescent-like CD8⁺ T cells.

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Sestrins induce natural killer function in senescent-like CD8<sup>+</sup> T cells.

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Sestrins induce natural killer function in senescent-like CD8+ T cells.

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Sestrins induce natural killer function in senescent-like CD8&lt;sup&gt;+&lt;/sup&gt; T cells.

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OmicsDI is part of the ELIXIR infrastructure

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Sestrins induce natural killer function in senescent-like CD8⁺ T cells.

Sestrins induce natural killer function in senescent-like CD8<sup>+</sup> T cells.