Mice depleted of CD8+ T and NK cells are resistant to injury caused by cecal ligation and puncture

Abstract

We previously showed that beta 2 microglobulin knockout mice depleted of NK cells by treatment with antiasialoGM1 (b2MKO/aAsGM1 mice) are resistant to sepsis caused by cecal ligation and puncture (CLP). b2MKO mice possess multiple immunological defects including depletion of CD8 þ T cells. This study was designed to determine the contribution of CD8 þ T and NK cell deficiency to the resistance of b2MKO/aAsGM1 mice to CLPinduced injury. b2MKO/aAsGM1 mice and CD8 knockout mice treated with anti-asialoGM1 (CD8KO/aAsGM1 mice) survived significantly longer than wild-type mice following CLP. Improved long-term survival was also observed in wild-type mice rendered CD8 þ T/NK cell-deficient by treatment with both anti-CD8a and antiasialoGM1. Blood gas analysis and body temperature measurements showed that CD8 þ T and NK cell-deficient mice have significantly reduced metabolic acidosis and less hypothermia compared to control mice at 18 h after CLP. CD8 þ T/NK cell-deficient mice also showed an attenuated proinflammatory response as indicated by decreased expression of mRNAs for IL-1, IL-6 and MIP-2 in spleen and heart. IL-6, KC and MIP-2 levels in blood and peritoneal fluid were also significantly decreased CD8 þ T/NK cell-deficient mice compared to controls. CD8 þ T/NK cell-deficient mice exhibited decreased bacterial concentrations in blood, but not in peritoneal fluid or lung, compared to wild-type controls. These data show that mice depleted of CD8 þ T and NK cells exhibit survival benefit, improved physiologic function and an attenuated proinflammatory response following CLP that is comparable to b2M/aAsGM1 mice. We previously demonstrated that b2 microglobulin knockout mice that were depleted of natural killer (NK) cells by treatment with anti-asialoGM1 (b2MKO/aAsGM1 mice) are resistant to systemic injury caused by cecal ligation and puncture (CLP). 1 Specifically, b2MKO/aAsGM1 mice exhibit improved survival, less metabolic acidosis, reduced hypothermia and better hemodynamic function compared to control mice following CLP. 1,2 These improvements in physiological function are associated with attenuation of the CLP-induced proinflammatory response.b2MKO/aAsGM1 mice have multiple immunological defects including an absence of CD8 þ T, natural killer (NK) and natural killer T (NKT) cells as well as deficient expression of the class I major histocompatability complex (MHC-I) and CD1 molecules. 1,3-5 One of our goals is to determine which of these immunological alterations confers resistance to the CLP-induced sepsis syndrome. We previously showed that adoptive transfer of CD8 þ T and NK cells into b2MKO/aAsGM1 mice will re-establish CLP-induced mortality. 1 In addition, we showed improved post-CLP survival in mice that are deficient of both CD8 þ T and NK cells. Based on this observation, we hypothesize that CD8 þ T and NK cell depletion contributes to the resistance of b2MKO/aAsGM1 mice to CLP-induced injury. To test this hypothesis, we directly compared CLP-induced mortality in b2MKO/aAsGM1 mice and CD8 þ T/NK cell-d...

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