title: 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.
authors.affiliation: Department of Surgery, Washington University School of Medicine, 660 South Euclid Ave., St. Louis, MO 63110, USA.
authors.forename: Paul E
authors.initials: PE
authors.lastname: Stromberg
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: Woolsey
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Clark
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Clark
authors.forename: Isaiah R
authors.initials: IR
authors.lastname: Turnbull
authors.forename: Kevin W
authors.initials: KW
authors.lastname: McConnell
authors.forename: Katherine C
authors.initials: KC
authors.lastname: Chang
authors.forename: Chun-Shiang
authors.initials: CS
authors.lastname: Chung
authors.forename: Alfred
authors.initials: A
authors.lastname: Ayala
authors.forename: Timothy G
authors.initials: TG
authors.lastname: Buchman
authors.forename: Richard S
authors.initials: RS
authors.lastname: Hotchkiss
authors.forename: Craig M
authors.initials: CM
authors.lastname: Coopersmith
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002470:Cell Survival; D004847:Epithelial Cells / Q000166:cytology / Q000502:physiology*; D018398:Homeodomain Proteins / Q000235:genetics / Q000276:immunology; D006801:Humans; D007413:Intestinal Mucosa / Q000166:cytology / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D018805:Sepsis / Q000276:immunology*; D013154:Spleen / Q000166:cytology
chemical_list: D018398:Homeodomain Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; C064658:RAG-1 protein