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. 2021 Sep 1;49(9):1513-1523.
doi: 10.1097/CCM.0000000000005047.

Expression of Exhaustion Markers on CD8+ T-Cell Patterns Predict Outcomes in Septic Patients Admitted to the ICU

Damien Guinault  1 , Marie-Laure Nicolau-Travers  2 , Stein Silva  3   4 , Olivier Cointault  1 , Barnabé Daniau  2 , Arnaud Del Bello  1 , Michael Peres  2 , David Rousset  4 , Julie Rieunier  2 , Laurence Lavayssiere  1 , Marie-Béatrice Nogier  1 , Edith Hourcastagnou  4 , Arnaud Mari  4 , Nassim Kamar  1   3 , François Vergez  2   3 , Stanislas Faguer  1   3   5
Affiliations

Expression of Exhaustion Markers on CD8+ T-Cell Patterns Predict Outcomes in Septic Patients Admitted to the ICU

Damien Guinault et al. Crit Care Med. .

Abstract

Rationale: There is an unmet need to improve the description of the state of T-cell exhaustion in patients with sepsis, its reproducibility and correlation with the outcomes before including immunotherapy (like recombinant interleukin-7 or immune checkpoint inhibitors) in the therapeutic armamentarium against sepsis.

Design: Observational prospective study.

Setting: Two ICUs in a teaching hospital (France).

Patients: Eighty patients with sepsis admitted to the ICU.

Interventions: Quantification of CD4+ and CD8+ T-cell exhaustion at days 1 and 3. Quantification of the exhaustion markers (programmed death [PD]-1, 2B4, and cluster of differentiation [CD] 160) on T cells, the number of CD4+ regulatory T cells (CD3+ CD4+ CD25hi CD127Lo cells), and the phorbol myristate acetate/ionomycin/ionomycin-induced cytokines production (tumor necrosis factor-α, interleukin-2, and interferon-γ).

Measurements and main results: Using unsupervised clustering analysis, patients could be split in three clusters according to their dominant pattern expression of exhaustion markers on CD8+ T cells (i.e., 2B4lowPD-1lowCD160low, 2B4hiPD-1hiCD160low, and 2B4hiPD-1lowCD160hi) regardless of their underlying morbidities. Only 2B4hiPD-1hiCD160low CD8+ T cells had cytokine production defect, whereas 2B4hi PD-1lowCD160hi pattern correlated with cytokine overproduction. Patients with a predominant "highly activated" 2B4hiPD-1lowCD160hi pattern did not develop secondary bacterial infections. By multivariate analysis, Simplified Acute Physiology Score 2 gravity score at day 1 (p = 0.003) and patterns of exhaustion markers on CD8+ T cells (p = 0.03) were associated with the risk of death. Neither the level of CD4+ regulatory T cells nor the CD4+ exhaustion patterns were associated with the outcomes.

Conclusions: Easy-to-use multicolor flow cytometry assessing 2B4, PD-1, and CD160 expression on CD8+ T cells at day 1 identifies septic patients with poor outcome and discriminates patient subsets in who immunomodulatory drugs should be tested.

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Conflict of interest statement

Dr. Vergez received funding from Pierre Fabre. Dr. Faguer received funding from Vifor Pharma. The remaining authors have disclosed that they do not have any potential conflicts of interest.

Comment in

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