CD4⁺lymphocytes control gut epithelial apoptosis and mediate survival in sepsis

Abstract

Lymphocytes help determine whether gut epithelial cells proliferate or differentiate but are not known to affect whether they live or die. Here, we report that lymphocytes play a controlling role in mediating gut epithelial apoptosis in sepsis but not under basal conditions. Gut epithelial apoptosis is similar in unmanipulated Rag-1(-/-) and wild-type (WT) mice. However, Rag-1(-/-) animals have a 5-fold augmentation in gut epithelial apoptosis following cecal ligation and puncture (CLP) compared to septic WT mice. Reconstitution of lymphocytes in Rag-1(-/-) mice via adoptive transfer decreases intestinal apoptosis to levels seen in WT animals. Subset analysis indicates that CD4(+) but not CD8(+), gammadelta, or B cells are responsible for the antiapoptotic effect of lymphocytes on the gut epithelium. Gut-specific overexpression of Bcl-2 in transgenic mice decreases mortality following CLP. This survival benefit is lymphocyte dependent since gut-specific overexpression of Bcl-2 fails to alter survival when the transgene is overexpressed in Rag-1(-/-) mice. Further, adoptively transferring lymphocytes to Rag-1(-/-) mice that simultaneously overexpress gut-specific Bcl-2 results in improved mortality following sepsis. Thus, sepsis unmasks CD4(+) lymphocyte control of gut apoptosis that is not present under homeostatic conditions, which acts as a key determinant of both cellular survival and host mortality.

Safety of ProbioticEscherichia coliStrain Nissle 1917 Depends on Intestinal Microbiota and Adaptive Immunity of the Host

“…This finding suggests that the adaptive immunity is dispensable in this context, although lymphocytes have been shown to substantially impact the proliferation and differentiation of the intestinal epithelium (41). This suggestion is based on our findings that Rag1 Ϫ/Ϫ mice raised under SPF conditions and exhibiting a physiologically mature microbiota did not have any bacteria in their MLN, liver, spleen, or lungs and that all of these mice survived oral challenge with high levels of E. coli strain Nissle 1917.…”

Selective blockade of interleukin-6 trans-signaling improves survival in a murine polymicrobial sepsis model*

“…The invasion of bacteria under septic conditions induces systemic inflammation and sepsis with subsequent organ failure (37,40). Importantly, the apoptosis rate of IECs is increased in patients with sepsis (41), and IEC apoptosis is crucial for mortality in CLP-induced murine sepsis (42)(43)(44)(45)(46). A recent study in C57BL/6 mice, which were also used in our experiments, showed that CD4 ϩ lymphocytes prevent IEC apoptosis and mortality after CLP (46).…”

“…Importantly, the apoptosis rate of IECs is increased in patients with sepsis (41), and IEC apoptosis is crucial for mortality in CLP-induced murine sepsis (42)(43)(44)(45)(46). A recent study in C57BL/6 mice, which were also used in our experiments, showed that CD4 ϩ lymphocytes prevent IEC apoptosis and mortality after CLP (46). Therefore, the mechanistically most important finding of the present study is that trans-signaling inhibition by sgp130Fc completely prevented sepsisinduced IEC apoptosis in the jejunum, whereas anti-IL-6 administration only led to a partial and nonsignificant reduction.…”

The Gut as the Motor of Multiple Organ Dysfunction in Critical Illness

“…While the presence or absence of lymphocytes does not impact gut epithelial apoptosis under basal conditions, sepsis-induced gut epithelial apoptosis is significantly higher in Rag −/− mice (which lack lymphocytes) than wild type mice, suggesting that lymphocytes play an anti-apoptotic role in the gut epithelium that is unmasked in sepsis (23). Subset analysis demonstrates that CD4+ T cells are responsible for the anti-apoptotic effect of the adaptive immune system on the gut epithelium.…”