Here we demonstrate that the transfer of alternatively activated myeloid cells benefits cognitive function in mice devoid of adaptive immunity. The improved cognitive function in this model is associated with alleviation of a skewed pro-inflammatory (M1) phenotype of meningeal myeloid cells, characteristic of mice deficient in normal meningeal T cell immune response. These results suggest that M2 cells could be utilized in future as a potential therapy for cognitive disorders associated with T cell dysfunction, such as HIV- dementia, age- related dementia, or ‘chemo-brain.’
The precise mechanism (whether cell migration of release of soluble factors to mediate this effect) underlying the changes in peripheral immunity as a result of i.c.v. injection of M2 cells, is beyond the scope of this paper and is being currently studied in the lab. Along these lines, this study aimed to address two major, and likely interconnected questions: First, are T cells working primarily through regulation of meningeal myeloid cell phenotype in their beneficial effect on cognitive function? Second, can immune-mediated benefit on cognitive function be achieved in a T cell-independent manner, or, in other words, can IL-4-activated myeloid cells circumvent the need for T cells and their derived IL-4?
We have shown that T cell derived IL-4 is the major soluble factor identified thus far that regulates meningeal immunity and contributes to cognitive function (Derecki et al., 2010
). However, since IL-4 has multiple potential targets—we have previously shown two, i.e. the phenotype of meningeal myeloid cells and BDNF expression by astrocytes—we did not know the extent to which the anti-inflammatory cytokines produced by T cell-induced meningeal myeloid cells might be important for cognitive benefit. Our current results indicate that myeloid cells may play a critical role in the T cell-mediated effect on cognitive function, at least under these experimental conditions. These results do not eliminate the possibility that the T cell-derived IL-4 regulation of astrocyte-produced BDNF is also involved in the T cell-mediated benefit in cognition. To perfectly address this question, a separate depletion of IL-4 receptor on meningeal myeloid cells or on astrocytes is needed. These experiments are currently underway in our laboratory, using IL-4R floxed mice (Marillier et al., 2010
It should also be noted that all of the experiments presented in this manuscript were performed in immune deficient, SCID, mice. These mice are shown to present a skewed pro-inflammatory myeloid phenotype in both periphery and meninges, due to the lack of T cells. It will be important to examine the effect of M2 cells on cognitive function under conditions of partial T cell malfunction more analogous to human conditions, such as in aged mice and mouse models of chemotherapeutic response. It is possible that in the presence of low levels of T cells, that would not be sufficiently supportive of cognitive function on their own, injection of M2 cells would result in even greater beneficial effect, since beyond their effect on innate immunity, M2 cells could also shift T cell immunity towards an anti-inflammatory TH2 phenotype, leading to a self-propagating beneficial response.
The i.c.v. injection of M2 cells did not yield a very significant behavioral effect, although a molecular effect was indeed observed. While prima facie surprising, this could, in fact, be due to the injury associated with the application of cells. Indeed, it is quite possible that the directly injected M2 cells would be marshaled by the CNS to participate in wound healing—rather than in support of cognition. The likelihood of this scenario is further supported by the fact that the number of cells injected was quite small (a necessity, given the tight constraints of intraventricular fluid pressure that limit injection volume), and that the injury was directly available to the skewed macrophages. Furthermore, microscopic examination post-injury shows significant intercalation of labeled cells within the brain parenchyma (not shown).
The effect of i.c.v. injection on peripheral immunity is intriguing, though not unprecedented. It has been recently shown that the CNS, via the splenic nerve, may be able to directly effect downregulation of macrophage-derived TNFα in spleen (Rosas-Ballina, PNAS, 2008). Whether the observations described in this paper are a result of meningeal or parenchymal immunity affecting peripheral immunity are unclear, and will require further study.
Collectively, we have shown here evidence that anti-inflammatory myeloid cells administered i.v. can significantly ameliorate cognitive impairment in mice lacking adaptive immune cells. While it has been amply demonstrated by our group and others that CD4+
T cells function in support of cognition (Derecki et al., 2010
), to our knowledge this is the first time that an immune-based T cell-independent boost of cognitive function has been demonstrated. The obviation of T cells as a necessary component in the support of learning and memory by the immune system is critical in terms of bridging the gap between bench and bedside application of basic neuroimmunology. Therapies that necessitate direct T cell manipulation are inherently risky. A boost of T cell function, if not well-controlled, can result in catastrophic autoimmunity, while suppression of T cell function increases the risk of cancer (Mantovani and Sica, 2010
; Sica et al., 2008
), and, as demonstrated recently, can also result in unanticipated inflammation and cognitive consequences (Derecki et al., 2010
). Myeloid cells, on the other hand, provide an opportunity to harness the therapeutic power of the immune system, and its ability to innately target anatomical sites of dysfunction—such as the meningeal spaces—without substantial risk of autoimmune consequences.