Susceptibility to programmed cell death in T-lymphocytes from septic patients: a mechanism for lymphopenia and Th2 predominance

doi:10.1016/S0006-291X(03)01482-7

Biochemical and Biophysical Research Communications

Volume 308, Issue 4, 5 September 2003, Pages 840-846

https://doi.org/10.1016/S0006-291X(03)01482-7 Get rights and content

Abstract

Sepsis causes lymphopenia which is inversely correlated with patient survival. The role of apoptosis-specific immune-activation and activation-induced cell-death in sepsis is incompletely understood. Fifteen septic patients and 20 healthy controls were included. T-cell proliferation was measured by [³H]thymidine uptake. Apoptosis and cell phenotype were determined by FACS. sTNFR1, sCD95, interleukin-1β converting enzyme (sICE), and interleukin (IL)-10 were measured by ELISA. PHA and CD3-driven T-cell proliferation were significantly decreased in septic patients. The percentages of CD3⁺ and CD4⁺ T cells and CD19⁺ B cells were significantly reduced. Percent memory T-cells (CD45RO⁺) and cells undergoing apoptosis (CD95⁺/annexin-V⁺) were significantly increased in sepsis. Moreover, sCD95, sTNFRI, and ICE were significantly increased. Anti-CD3 antibody triggering induced a 56% increase of CD4 T-cell death in septic patients vs. 7.5% in controls relative to IgG. Serum level of IL-10, a Th2 cytokine, was enhanced. These findings strongly suggest that in septic patients Th1 T-cells are selectively susceptible to undergo apoptosis. This observation provides an additional pathophysiological concept in the genesis of Th2 dominance.

Section snippets

Methods

Patients and clinical features. The study protocol was approved by the institutional review board of the University of Vienna Medical School, General Hospital. All study and control subjects or their legal designees signed a written informed consent. Patients were classified as septic based on the international criteria of the ACCP/SCCM consensus conference [Crit. Care Med. 20 (6) (1992) 864–874]. Blood sampling was performed meeting the exclusion criteria of freedom of hemofiltration,

T-cell proliferation

Fig. 1 demonstrates a significant reduction of T-cell proliferative capacity in response to PHA in septic patients—indicated by the mean stimulation index (SI)—as compared to healthy controls (P<0.001). As further shown in Fig. 1, the SI of T-cells from septic patients vs. controls was markedly reduced following activation with anti-CD3 mAb (P<0.001).

Changes in T-cell phenotype

The amount of CD3⁺ and CD4⁺ T-cells in patients with sepsis was significantly reduced when compared to controls (Table 2).

The results depicted in

Discussion

We have found that sepsis is accompanied by defects in cellular immunity that relate to an aberrant state of T-cell activation involving the CD95 pathway, shedding of death inducing receptors, and pronicity of CD4⁺ T-cells to undergo AICD. Our findings suggest a novel immunological mechanism that accounts for the observed lymphopenia, Th2 predominance, and subsequent immunodysfunction in sepsis.

Similar to HIV-1 infection sepsis is associated with depletion of T-cells and immune dysfunction due

Acknowledgements

Drs. G. Roth and B. Moser were responsible for laboratory work and data evaluation and contributed equally to this paper. Dr. M. Brunner and S. Gerlitz RN performed the laboratory work. Drs. C. Krenn and M. Haisjackl were responsible for clinical management. Prof. E. Wolner and Prof. G. Boltz-Nitulescu provided infrastructural support. Dr. Hendrik Jan Ankersmit designed and coordinated the study and edited the paper.

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Susceptibility to programmed cell death in T-lymphocytes from septic patients: a mechanism for lymphopenia and Th2 predominance

Abstract

Section snippets

Methods

T-cell proliferation

Changes in T-cell phenotype

Discussion

Acknowledgements

Mol. Med. Today

Blood

Lancet

Immunity

Blood

J. Immunol. Methods

J. Biol. Chem.

Cell

Cell

Search for sepsis drugs goes on despite past failures

Science

Apoptosis in lymphoid and parenchymal cells during sepsis: findings in normal and T- and B-cell-deficient mice

Crit. Care Med.

Apoptotic cell death in patients with sepsis, shock, and multiple organ dysfunction

Crit. Care Med.

Sir Isaac Newton, sepsis, SIRS, and CARS

Crit. Care Med.

Sepsis-induced apoptosis causes progressive profound depletion of B and CD4+ T lymphocytes in humans

J. Immunol.

Expression of Fas (CD95) and Fas ligand on peripheral blood mononuclear cells in critical illness and association with multiorgan dysfunction severity and survival

Crit. Care Med.

The Fas death pathway as a mechanism of multiple organ dysfunction syndrome: not so fast

Crit. Care Med.

Sepsis-induced apoptosis causes progressive profound depletion of B and CD4⁺ T lymphocytes in humans