1 Department of Psychology, Columbia University, New York; 2 Department of Pathology and Cell Biology, Columbia University College of Physicians and Surgeons, New York; and 3 Department of Psychology, Barnard College, New York, New York Submitted 3 November 2008 ; accepted in final form 19 December 2008 As central nervous system residents, mast cells contain many cytokines and are localized primarily near large blood vessels in the diencephalon and within the leptomeninges, making them candidates for immune to neural "cross talk." Using mast cell-deficient Kit W-sh/W-sh mice, we assessed the role of these cells in the thermoregulatory component of the immune response to lipopolysaccharide (LPS). Kit W-sh/W-sh and wild-type (WT) mice differed in several respects in response to injection of a high dose of LPS (1 mg/kg ip). Core temperature (T c ) of WT mice decreased by 3°C, whereas Kit W-sh/W-sh mice did not become hypothermic but instead exhibited pronounced low-frequency T c oscillations around their baseline temperature. In addition, Kit W-sh/W-sh mice had lower levels of whole brain TNF- but no differences in IL-1β, IL-6, IFN- , or histamine compared with WT mice following injection of the high dose of LPS, consistent with the role of TNF- in sepsis. Kit W-sh/W-sh mice had increased resistance to LPS, and some survived a dose of LPS that was lethal in littermate controls. In contrast, Kit W-sh/W-sh and WT mice were similar in other aspects, namely, in the hyperthermia following injection of TNF- (1.5 µg icv), reduced nighttime T c and locomotor activity (to 1 mg/kg LPS), response to a low dose of LPS (10 µg/kg ip), and response to subcutaneous turpentine injection. These results indicate that mast cells play a role in the regulation of thermoregulatory responses and survival following sepsis induction and suggest a brain site of action. tumor necrosis factor- ; interleukins; interferon- ; histamine; mast cell-deficient sash mice; hypothermia Address for reprint requests and other correspondence: R. Silver, Dept. of Psychology, Columbia Univ., 1190 Amsterdam Ave., 406 Schermerhorn Hall, MC 5501, New York, NY 10027 (e-mail: qr{at}columbia.edu )