MICE DEPLETED OF Αβ BUT NOT Γδ T CELLS ARE RESISTANT TO MORTALITY CAUSED BY CECAL LIGATION AND PUNCTURE

Abstract

The present study was undertaken to determine whether the mice depleted of alphabeta or gammadelta T cells show resistance to acute polymicrobial sepsis caused by cecal ligation and puncture (CLP). T-cell receptor beta knockout (betaTCRKO) and T-cell receptor delta knockout (deltaTCRKO) mice were used. An additional group of mice was treated with an antibody against the alphabeta T-cell receptor to induce alphabeta T-cell depletion; a subset of alphabeta T cell-deficient mice was also treated with anti-asialoGM1 to deplete natural killer (NK) cells. The mice underwent CLP and were monitored for survival, temperature, acid-base balance, bacterial counts, and cytokine production. The betaTCRKO mice and the wild-type mice treated with anti-beta T-cell receptor (anti-TCRbeta) antibody showed improved survival after CLP compared with wild-type mice. The treatment of alphabeta T cell-deficient mice with anti-asialoGM1further improved survival after CLP, especially when the mice were treated with imipenem. The improved survival observed in alphabeta T cell-deficient mice was associated with less hypothermia, improved acid-base balance, and decreased production of the proinflammatory cytokines interleukin (IL) 6 and macrophage inflammatory protein (MIP) 2. Compared with wild-type controls, the overall survival was not improved in deltaTCRKO mice. The concentrations of IL-6 and MIP-2 in plasma and cytokine mRNA expression in tissues were not significantly different between wild-type and deltaTCRKO mice. These studies indicate that mice depleted of alphabeta but not of gammadelta T cells are resistant to mortality in an acutely lethal model of CLP. The depletion of NK cells caused further survival benefit in alphabeta T cell-deficient mice. These findings suggest that alphabeta T and NK cells mediate or facilitate CLP-induced inflammatory injury.

CD6 binds to pathogen-associated molecular patterns and protects from LPS-induced septic shock

“…It cannot be ruled out, however, that the antiinflammatory effects of rsCD6 on LPS-induced septic shock may also result from its inhibitory effects on different cell subsets involved in the outcome of sepsis such as CD8 T cells and natural killer cells (35). In fact, rsCD6 has been shown to inhibit human antigen-presenting cell-T cell interactions (17,36), and CD6 is known to be expressed on natural killer cells (36).…”

Células con propiedades inmunoreguladoras y su impacto en la patogénesis de la sepsis

“…Ratones defi cientes de células NK que cursan con un proceso de sepsis son más resistentes a la muerte inducida por este síndrome, lo cual fue asociado a la atenuación de la respuesta infl amatoria 38,39 . De hecho, la activación de las células NK induce la secreción de citoquinas como IFN- y FNT-, que contribuyen a la falla multisistémica y al cuadro clínico del shock séptico.…”

“…Ratones defi cientes de esta población celular son más susceptibles a desarrollar sepsis, lo que se ha asociado con una disminución plasmática de citocinas pro-infl amatorias como IFN- y FNT-, así como al establecimiento de un estado de imununosupresión que contribuye a la mortalidad de estos ratones 60,61 . En contraste, en otros estudios no se ha observado un efecto en la supervivencia o producción de citoquinas en ratones defi cientes de LTgd que cursan con un proceso de sepsis (LPC) 38 , mientras que en otros se sugiere que la defi ciencia de LTgd disminuye la morbilidad de ratones que cursan con infecciones bacterianas 62 . Adicionalmente, algunas alteraciones en la función y en el porcentaje de esta población celular se han observado en pacientes con shock séptico y trauma 63,64 .…”

Implications of IL-6 Targeting Therapy for Sepsis

“…Our group identified that Arid5a, which is a counteractive partner to Regnase-1, is a stabilizer in terms of binding to the 3'-UTR of IL-6 mRNA [5]. The expression of Arid5a is quickly induced in macrophages upon LPS stimulation ( Figure 1).…”

“…However, exaggerative elevation of cytokine production might lead to the onset or development of acute inflammatory diseases. Sepsis is severe systemic inflammatory response upon infection, leading to excessive pro-inflammatory cytokine production such as IL-6, TNFα and IFNγ [4,5]. Upon infection, IL-6 and TNFα are highly expressed by innate immune cells including macrophages and dendritic cells, whereas IFNγ is produced by IL-12−derived T helper type 1 (Th1) cells.…”