Sepsis induces extensive lymphocyte apoptosis that contributes to immunosuppression and mortality. Activation of the canonical
NF-kappaB pathway, however, prevents
TNF-alpha-induced lymphocyte apoptosis. In this study the function of canonical
NF-kappaB in T cells was studied in the context of murine
sepsis. Upon cecal
ligation and
puncture (CLP),
NF-kappaB DNA binding activity in thymocytes declines relative to
sham-operated mice. This decline in
NF-kappaB activity is most likely due to posttranslational modifications such as deacetylation of p65. In parallel, cleavage of
procaspase-3 is increased, whereas expression of
NF-kappaB-dependent antiapoptotic genes Bcl-xL and c-IAP2 is suppressed upon
sepsis induction. Interestingly, adoptive transfer of
IkappaBalpha-deficient fetal liver stem cells into sublethally irradiated lymphopenic host mice reduced the decline in thymocyte survival, increased peripheral T cell numbers, and improved the mortality rate relative to wild-type reconstituted hosts after cecal
ligation and
puncture. In conclusion, lymphocyte-directed augmentation of canonical
NF-kappaB ameliorates immunosuppression during murine
sepsis. These data provide evidence for a new approach in
sepsis therapy.