Friday, November 25, 2011

gut instinct is depressing

does Immune system has any role besides protecting the body from infections? In my opinion, the answer is probably NO. Once in a while, however, you may find a study claiming otherwise (for example, study claiming that adaptive immune system improves neuron function and memory (1). These type of studies are usually based on observations derived from mice with a defective immune system (missing one or several components of immune system). The main challenge to these type of conclusions is the fact that because normal body harbors myriad varieties of microbes (in the gut, skin, oral cavity, etc.), then even a simple alteration of immune system may indirectly affect other tissue's function though its direct (missing)impact on microbiota. In order to properly address the involvement of immune system in other tissues function experiment should be carried out in the absence of microbiota, for example, in germ-free mice.

If you interested to know more whether immune system could affect other tissue's function and also to illustrate my point, I will recommend reading the following paper that appeared recently in Nature Medicine. This study, by Shulzhenko N and Morgun A et al., looked at intestinal tissue function in the absence of B cells (2). Using several lines of B cell or immunoglobulin (Ig) knock-out (KO) mice and gene microarray analysis, they found that there was very similar changes of intestinal tissue in mice missing B cells or IgA compared to wild type littermates (Fig 2c). In general, genes involved in defense were up-regulated and genes involved in metabolism were down-regulated in B cell KO mice compared to wild type littermates. This may have implied that B cells modulate intestine tissue function. However, to rule out indirect effect of microbiota, they carried out the same experiment in germ-free B cell KO or germ-free wild type mice. As expected, the difference in gene expression of intestinal tissue between B cell KO and wild type mice disappeared on germ-free background (Fig 3c,d). Of note, similar down-regulation of intestinal tissue metabolism occurred in both B cell KO and RAG KO mice (that lacks T cells as well) but it did not occur on germ-free background. These data suggested that improper activation of adaptive immune system in the absence of B cells were not responsible for down-regulation of intestinal metabolism and that microbiota was involved. Because gene expression profile of B cell KO mice was very similar to gene expression profile of intestinal tissue derived from mice with intestinal epithelial-specific deletion of GATA4 transcription factor, the authors concluded that altered microbiota (as a result of lack of B cells/IgA) directly affected intestine tissue metabolism. They also supported this conclusion by profiling gene expression of isolated intestinal epithelial cells from B cell KO mice and using mouse intestinal cell line treated with different inflammatory stimuli. In my opinion, the caveat of this interpretation is the fact that (a) gut tissue contains diverse set of innate immune cells (for example, lymphoid-tissue inducer-like cells) that could have affected gut metabolism and (b) intestinal epithelial cells isolated from B cell KO mice might had already received signals from these innate immune system (and not directly from microbiota) (in Fig. 5c). In my opinion, the better way to support their conclusion would have been to isolate intestinal epithelial cells from germ-free mice and treat them with different microbes or their components.

Overall, this study is one of best example of how proper experimental approach reveals the hidden effect of microbiota on intestinal tissue in the absence of one component of immune system, in this case the absence of B cells (and IgA).


Sunday, November 20, 2011

A freak of Nature

Today I am going to introduce a new discussion topic I call “right paper wrong journal”.

Scientist are looking for two things in the journal editor: integrity and good judgment. In many occasions, we have a situation when a publication of a particular paper represents editor's less than a good judgment. By judgment here I mean a relevance and a value paper brings to the journal readers. Paper can be well designed and properly done but it may not make a significant contribution for the knowledge advancement. 

Here is the example of such paper that was recently published in Nature (Nature is widely regarded a the world's most prestigious science journal). In this paper by Christine Moussion and Jean-Philippe Girard (1), the authors showed that in vivo a proper maintenance of lymph node (LN)-specific endothelial cells, called high endothelial venules (HEV), requires their interaction with dendritic cells through lymphotoxin-β receptor. As a functional outcome, the authors showed that in the absence of dendritic cells LNs had reduced cellularity due to a reduced capacity of lymphocytes to adhere to the HEV and enter the LN. However, no data is provided how this changes would have affected any meaningful immunological response. Any way, absence of dendritic cells by itself (independent of HEV functionality) will make an initiation of antigen-specific immune response almost impossible. Is there any reason why this paper could have not be published in Journal of Immunology?


Sunday, November 13, 2011

memory CD8 T cell Id(3)'d

The hallmark of an adaptive immune system is to respond more robustly when challenged again with the same antigen. It is called a memory response. CD8 T cells are the best studied model of antigen-specific CD8 T cell population expansion and contraction during antigenic challenge. Effector CD8 T cells that survive contraction phase form memory pool. It is estimated that only around 1-10% of a peak response CD8 T cells survive the memory bottleneck. Understanding the molecular mechanisms that allow a particular CD8 T cell to survive contraction phase will help to design better vaccination strategy. Many factors have been described that correlates (control) with memory CD8 T cells formation (for example, IL-7Ralpha or IL-2Ralpha expression). However so far no one came up with a clear model that could explain what controls the controllers. In my opinion, the answer will be found in the T cell receptor (TCR) specificity and in precise understanding how strength of signaling is translated into individual CD8 T cell fate.

If you interested to know more about mechanisms of CD8 T cell memory formation, I would recommend reading the following two papers recently published in Nature Immunology. Both papers, one by Cliff Yang et al. (1), and another by Yun Ji et al.(2), showed that the expression of transcription factor Id3 is necessary for memory CD8 T cells formation. Following data are critical for an analysis: in paper by Cliff Yang et al., Fig. 1e shows that expression level of Id3 is higher when increasing number of CD8 T cells are transferred. This may imply that Id3 is maintained more easily in CD8 T cells that receives minimal stimulation. Fig. 2B shows that Id3high CD8 T cells produce more IL-2 compared Id3low CD8 T cells. Fig. 3E shows that Id3high CD8 T cells are maintained in higher numbers upon adoptive transfer compared to Id3low CD8 T cells. Fig. 5A shows that Id3-deficient transgenic CD8 T cells (on wt background) are impaired in survival after viral infection compared to Id3-sufficient OT-I cells (3-fold reduction at day 60). In paper by Yun Ji et al., however, survival disadvantage of Id3-deficient transgenic CD8 T cells (on RAG KO background) is more pronounced compared to Id3-sufficient transgenic CD8 T cells. This may imply that TCR affinity (OT-I vs. pmel-1 or wt vs. RAG KO background) determines the absolute need for Id3 for memory formation.

David Usharauli