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

Paul E. Stromberg^*,1, Cheryl A. Woolsey^*,1, Andrew T. Clark^*, Jessica A. Clark^*, Isaiah R. Turnbull^*, Kevin W. McConnell^*, Katherine C. Chang, Chun-Shiang Chung, Alfred Ayala, Timothy G. Buchman^*, Richard S. Hotchkiss and Craig M. Coopersmith^*,2

^* Department of Surgery and

Department of Anesthesiology, Washington University School of Medicine, St. Louis, Missouri, USA; and

Department of Surgery, Rhode Island Hospital and Brown University School of Medicine, Providence, Rhode Island, USA

²Correspondence: Washington University School of Medicine, 660 South Euclid Ave., Campus Box 8109, St. Louis, MO 63110, USA. E-mail: coopersmithc{at}wustl.edu

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⁺, , 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.—Stromberg, P. E., Woolsey, C. A., Clark, A. T., Clark, J. A., Turnbull, I. R., McConnell, K. W., Chang, K. C., Chung, C.-S., Ayala, A., Buchman, T. G., Hotchkiss, R. S., Coopersmith, C. M. CD4⁺ lymphocytes control gut epithelial apoptosis and mediate survival in sepsis.

Key Words: crosstalk • intestine • Bcl-2 • cell death • cecal ligation and puncture