Increased inducible apoptosis in CD4 super(+) T lymphocytes during polymicrobial sepsis is mediated by Fas ligand and not endotoxin

• Published in: Immunology 1999-05, Vol.97 (1), p.45-55
• Main Authors: Ayala, A, Chung, C-S, Xu, Y X, Evans, T A, Redmond, K M, Chaudry, I H
• Format: Article
• Language: English
• ISSN: 0019-2805

Recent studies suggest that increased lymphocyte apoptosis (A sub(o)) detected in peripheral blood T cells from burn patients appears to contribute to decreased lymphocyte immunoresponsiveness. However, while it is known that sepsis induces a marked depression in the splenocyte immune response (i.e. decreased interleukin-2, interferon- gamma production and proliferation) in response to the T-cell mitogen concanavalin A (Con A), it is unknown whether this depression is associated with an increase in inducible A sub(o) and if so, which mediators control this process. To assess this, splenocytes were harvested from mice at 24 hr (a period associated with decreased Con A response) after the onset of polymicrobial sepsis [caecal ligation and puncture (CLP)] or sham-CLP (Sham) and then stimulated with 2.5 mu g Con A/ml (24 hr). Septic mouse splenocytes stimulated with Con A, while not showing a change in their phenotypic make-up, did exhibit a marked increase in the percentage of splenocyte that were A sub(o) super(+) which was associated with altered cytokine release. This appears to be due to an increase in the percentage of A sub(o) super(+) cells in the CD4 super(+) CD8 super(-) population and was associated with enhanced Fas antigen expression as well as an increase in mRNA for the Fas-FasL gene family. To determine if the changes in A sub(o) are due to either endotoxin (a product of Gram-negative bacteria seen in CLP mice) or the expression of Fas ligand (FasL; a mediator of activation-induced lymphocyte A sub(o)), a second set of studies examining Con A-inducible A sub(o) was performed with splenocytes harvested from septic endotoxin-tolerant C3H/HeJ and the FasL-deficient C3H/HeJ-Fasl super(gld) mice. The results show that increased splenocyte A sub(o) detected following CLP is due to a FasL-mediated process and not to endotoxin. Thus the inadvertent up-regulation of FasL-mediated splenocyte A sub(o) may contribute to the depression of splenocyte immune responses seen during polymicrobial sepsis.