Inhibition of CD1d activation suppresses septic mortality: a role for NK-T cells in septic immune dysfunction.
BACKGROUND
Studies indicate that following septic insult there is development of generalized immune dysfunction in T cells, B cells and phagocytes, which is thought to contribute to morbidity and mortality. Specifically, there is a shift in the lymphocytes of septic animals toward an increased release of Th2 cytokines. NK-T cells have been shown to contribute to propagation of the Th2 response. The influence of NK-T cells on the immune response to septic challenge is poorly understood. In this study, we examine whether NK-T cells contribute to the immune dysfunction seen following the onset of polymicrobial sepsis, as produced by cecal ligation and puncture (CLP).


METHODS
Male 129S1/SvImJ mice were pretreated with either rat IgG (isotypic control) or monoclonal antibody to CD1d (clone 1B1) (0.5 mg), which blocks signaling/antigen presentation via the CD1d cell surface receptor, thereby, ablating the activation and differentiation of the NK-T cells. Septic survival with and without anti-CD1d (CLP/CD1d) pretreatment was assessed. Mice sacrificed 24 h after CLP were assessed for change in splenic %NK-T cell (via flourescense activated cell sector) and for splenic, hepatic, and lymphoid/macrophage production of pro-inflammatory or anti-inflammatory cytokines (via enzyme-linked immunosorbent assay).


RESULTS
Administration of anti-CD1d reduced septic mortality 35% at 6-10 d (n = 23 mice/group) (P <.05). There was a consistent increase in the %CD3(+) NK1.1(+) cell population (NK-T cells) in septic mice (1.706%), which was markedly suppressed by pretreatment with anti-CD1d (0.592%). IL-6 and IL-10 levels were suppressed by anti-CD1d in the spleen and blood.


CONCLUSIONS
Together these findings imply not only that NK-T cells may play a role in mediating the immune suppression seen in bacterial sepsis, but that inhibition of their activation promotes survival to septic challenge.
Division of Surgical Research, Department of Surgery, Lifespan-Rhode Island Hospital, Rhode Island, USA.
Rebecca J
RJ
Rhee
Stacey
S
Carlton
Joanne L
JL
Lomas
Crystal
C
Lane
Laurent
L
Brossay
William G
WG
Cioffi
Alfred
A
Ayala
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D018949:Antigens, CD1 / Q000276:immunology*; D055610:Antigens, CD1d; D002432:Cecum / Q000601:surgery; D005434:Flow Cytometry; D007074:Immunoglobulin G / Q000008:administration & dosage; D007371:Interferon-gamma / Q000032:analysis; D016753:Interleukin-10 / Q000032:analysis / Q000097:blood; D018664:Interleukin-12 / Q000097:blood; D015850:Interleukin-6 / Q000032:analysis / Q000097:blood; D007694:Killer Cells, Natural / Q000276:immunology*; D008026:Ligation; D008264:Macrophages / Q000737:chemistry; D008297:Male; D051379:Mice; D018805:Sepsis / Q000276:immunology* / Q000401:mortality*; D013154:Spleen / Q000737:chemistry / Q000166:cytology; D015996:Survival Rate; D018418:Th2 Cells / Q000276:immunology
D000911:Antibodies, Monoclonal; D018949:Antigens, CD1; D055610:Antigens, CD1d; D007074:Immunoglobulin G; D015850:Interleukin-6; D016753:Interleukin-10; D018664:Interleukin-12; D007371:Interferon-gamma