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The complement system limits systemie T celi actwation.

It is well recognized that the clearance of apoptotic cells through iC3b opsonisation and CR3 phagocytosis can be accompanied by a reduction in the expression of co-stimulatory molecules and an impaired maturation of dendritic cells (Morelli et al., 2003). The reeruitment of large numbers of NK cells may therefore be critical for optimal DC actwation and subseąuent induction of T celi responses in these low-inflammation conditions. Given that NK cells can cross-talk with DCs to mediate their actwation, we wanted to assess their actwation status after transient inhibition of the complement system. We did not observe any modulation of CD86 expression levels in spienić or draining lymph node DCs (Fig. 3A). We then sought to determine if the enhanced NK celi proportions at the tumor site could nevertheless lead to an inereased T celi actwation. The majority of CD4⁺ and CD8⁺ T cells present in the tumor were of the effector/effector memory phenotype and their proportions did not change following complement inhibition. However, in the spleen, CVF-mediated depletion of complement led to reduced proportions of naive T cells associated with inereased proportions of effector CD4⁺ and CD8⁺ T cells (Fig. 3B). It is therefore likely that in the absence of complement proteins, functional DCs have access to morę tumor antigens due to inereased NK-mediated celi lysis allowing for a better presentation to CD8⁺ T lymphocytes.

The enhancement of tumor-speciflc CTL responses in decomplemented mice is NK-dependent.

It has been reported that complement components can interfere with the binding of NK cells to raonoclonal antibodies (mAbs) used in certain cancer treatments thus limiting NK cell-mediated lysis of antibody-coated target cells (Wang et al., 2008). It was also showed that this inhibition was dependent on C3b, likely by its binding to CR3 molecules abrogating signaling via Fcy receptor 111 (CD 16) (Wang et al., 2008). Furthermore, depletion of complement has been shown to enhance survival rates following mAb therapy in a syngeneic mouse model of lymphoma (Wang et al., 2009).

To ascertain if the enhanced tumor control we observed in decomplemented mice was a direct consequence of the inereased proportions of NK cells in these mice, we depleted NK

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