Sunday, September 25, 2011

blind love: neuro-immune chemistry

Immune and nervous systems share two unique characteristics: (a) both systems undergo adaptive “education” to discriminate between self and nonself signals and (b) both systems have “memory” to it.

So far few research papers had been published that addressed the question how these two complex systems interact with each other. For example, one paper claimed that T cells can promote neuronal re-generation and hence contribute to the learning process (1). These study was based on evidence that T cell transfer into immunodeficient mice improved neuronal generation. In my opinion, this interpretation fails to take into account the fact that T cell transfer into immunodeficient mice affect not just brain function but for instance, gut permeability too. Why is it important? It is well known that endotoxin (LPS) level in the blood affects brain function. LPS level in the blood, in turn, is influenced by gut permeability, that in turn, is influenced by immune system status. T cell transfer into immunodeficient mice would allow differentiation of gut-homing T cells that may have reduced gut permeability thus indirectly affecting brain function.

If you are interested in neuro-immune research, then I will recommend to read the following two papers recently published in Science (2, 3).

1st paper from Kevin Tracey's Lab provided the direct evidence that the presence of specialized, acetylcholine-secreting memory T cells were necessary and sufficient to relay signals from nervous system to the immune (2).

2nd paper from Paul Kubes Lab showed that CD1d-deficient mice (that lack all NKT cells) were more susceptible to stroke-associated immunosuppression compared to wild-type mice (3). This immunosuppression could be prevented by stimulating NKT cells or blocking noradrenalin signaling in these cells because this protective effect of noradrenalin blockade was abolished in CD1d-deficient mice. It is of note that both NKT presence and simultaneous blockade of noradrenalin signaling in these cells was necessary for full protection. This is a kind of paradox. However, because there are two types of NKT cells in mice, there may be a simple explanation. So it will be interesting to compare CD1d-deficient mice to Jalpha18-deficient mice that lack only one type of NKT cells. In my opinion, NKT cells transfer into CD1d-deficient mice would have provided more direct evidence of protective role of this innate NKT cells.

David Usharauli

Sunday, September 18, 2011

OX40/CD30 lay off Foxp3

 Since it's discovery in 2001, a transcription factor called Foxp3 has been recognized as a master regulator of autoimmune disease. It's total deficiency in CD4 T cells has such a profound effect that mouse that lacks it usually die of inflammatory multi-organ failure within 3 weeks of birth.

We don't know how exactly Foxp3+ CD4 T cells prevent autoimmunity. Currently, there is no mechanistic model that could satisfactorily explain their function. Even at the theory level, Foxp3+ T cell role is either totally ignored/dismissed (for example, in SNS model) or characterized as an immune class-specific effector/memory T cells (for example, in danger model). In short, the viable concept of negative regulation of immune system by antigen-specific Foxp3+ CD4 T cells is yet to come.

If you are interested in Foxp3+ T cell biology, I recommend reading a new study recently published in Journal of Experimental Medicine (1). This study, by Fabrina M. Gaspal and et al, made an interesting observation that mice triple deficient in OX40/CD30/Foxp3 are healthy. It appears that OX40/CD30 pathways control autoimmune potential of self-specific T cells. The simple explanation I favor is that in the absence of OX40/CD30 signaling, effector/memory T cell differentiation is impaired in general and as a consequence, self-specific T cells loose the capability to damage the tissue. Of course, the one caveat of the paper is that we have no idea whether those triple deficient mice are capable of mounting a proper immune response to non-self antigenic challenge or infection. If they cannot, then the absence of autoimmunity is the direct consequence of immunodeficiency (similar to gamma-c receptor deficient mouse model). However, if they could respond to non-self antigenic challenge or infection, then this model has made an unique contribution to our understanding of Foxp3 biology.

David Usharauli