microbiota greenlights brain inflammation

For the past few years published literature in immunology became enriched in studies related to commensial microbiota found mainly in mammalian gut. There is one simple explanation for this renewed interest in commensial microbiota: discovery and characterization of Toll-like receptors (TLRs) in late 90's (recognized by Nobel prize in Physiology or Medicine 2011). TLRs opened the door to study microbiota-host interaction at molecular level and made it easy to explain experimental observations mechanistically. In general, commensial microbiota could influence immune system in two ways: first, it could provide the antigenic material for adaptive immune system activation (T or B cells activation) and second, it could provide TLR ligands for innate immune system activation.

If you are interested to know more about commensial microbiota-host interaction, I will recommend to read the following article recently published in Nature. This study by Kerstin Berer et al. (1), examined the effect of commensial microbiota on the development of brain autoimmune disease in SJL/J TCR transgenic mice. In this mouse, if housed in a regular laboratory mouse facility, brain inflammation occurs spontaneously and is mediated by combined effect of MOG-specific T cells and B cells. However, according to this study, this type of brain inflammation does not occur in this mouse made germ-free (in sterile, microbiota free state). The disease development in this mouse require the presence of MOG protein because in its absence there is no brain inflammation irrespective of presence of absence of commensial microbiota. This results suggest that microbiota provide antigen-independent effect leading to stimulation of MOG-specifc T and B cells. However, how microbiota does it is not clear. The authors showed that there is reduction of IL-17 producing T cells in the gut of germ-free mouse. However, the authors provide no direct evidence whether IL-17-producing T cells play any role in disease development.

David Usharauli                  

missing link gets 11 points

Innate immune system detects the presence of structural components of microbes/viruses/fungi and alerts the adaptive immune system. Toll-like receptors are so far the most studied class of these innate sensors (recognized with Nobel Prize in Physiology or Medicine 2011). However, there is another class of innate sensors represented by cytosolic NOD-like receptors (NLRs)/caspase-1 pathway. This class of sensors form so called inflammasome complexes that detect virulence factors derived from microbes/viruses/fungi. Activation of caspase-1 cleaves pro-IL-1beta into active IL-1beta, releases active IL-1alpha and causes cell death called pyroptosis. Earlier studies have shown that caspase-1 deficient mice are resistant to endotoxin-induced septic shock, a mouse model of sepsis.

If you are interested to know more about inflammasome, I will recommend to read the following article published in Nature. I personally think that this article is the best immunology paper published so far this year. This study by Nobuhiko Kayagaki et al. (1), examined the activation of inflammasome by cholera toxin component B (CTB). While LPS-primed macrophages from B6 and other commonly used mice strains responded to CTB by producing active IL-1beta, LPS-primed macrophages from 129S6 strain failed to respond to CTB. It turned out that 129S6 mouse has a mutation in caspase-11 gene. By creating caspase-11 deficient B6 mice the authors confirmed that the failure of 129S6 mice to respond to CTB was indeed related to caspase-11 mutation. In addition to CTB, both caspase-11 deficient B6 mouse and 129S6 failed to release IL-1beta (via caspase-1 pathway) in response to E. coli, C. rodentium and V. cholerae, but responded to ATP, LLO, MSU, nigericin and others. Failure to activate this caspase-11-dependent, but caspase-1-independent non-canonical inflammasome pathway resulted in reduced IL-1alpha release and reduced cell death (pyroptosis). By analyzing available caspase-1 deficient mice, the authors showed that they were deficient in caspase-11 as well, because they were derived from 129 mouse ES cells. These results raised the question about interpretation of the data derived from caspase-1 deficient mice experiments. By creating caspase-1 KO/caspase-11 transgenic mouse, the authors showed finally that endotoxin-induced septic shock was mediated by caspase 11, not caspase 1, as originally thought. How caspase-11 mediates LPS toxicity is not clear. It could be related to pyroptosis.

This serendipitous discovery will lead to the better understanding of sepsis immuno-pathology and ultimately will lead to improvement in treatment outcome.

David Usharauli     

CD8 T cells: too selfish to share IL-2

CD8 T cells play a pivotal role in body's defense against viral infections. While it is relatively easy to see activation of CD8 T cells against a real infectious virus, nominal, non-replicative antigens (used in many vaccines) have a hard time to mimic it. In general, CD4 T cell help and antigen presentation by dendritic cell (DC) are required to activate CD8 T cell. In 1998, three articles published back to back in Nature showed that one mechanism of CD4 T cell help was through CD40L-triggered DC (called licensing). Later, another mechanism has been discovered: help through IL-2 signaling in CD8 T cells. Both mechanisms, however, created some confusion in scientific community. The point is that both CD40L as well as IL-2 can be expressed by all three types of cell involved in CD8 T cell activation: CD4 helper cell, DC and CD8 T cell. The debate then and now is about what kind of cell (CD4, DC, CD8) has to express CD40L or IL-2 to provide biologically significant help for CD8 T cell activation.

If you are interested to know more about “help” signal to CD8 T cell, I will recommend to read the new article from Steve Schoenberger's Lab (one of the author of the original 1998 paper) published recently in Nature Immunology. In the study by Sonia Feau et al (1), the author showed that CD8 T cell activation or it's memory formation was comparable whether CD4 T cells could express IL-2 or not. CD40L blockade, however, inhibited CD8 T cell response. No data are provided, however, to understand whether CD40L expression on CD4 T cell (or other cell types) was involved here. The critical data are in Fig. 3 and 4. In Figure 3, using infectious virus, the author showed that IL-2-deficient CD8 T cells expanded less compare to IL-2-sufficient CD8 T cells. Interestingly, IL-2-deficient CD8 T cells behaved exactly as if IL-2-sufficient CD8 T cells (in mouse)-depleted of CD4 T cells. Another critical point is that in CD4 T cell-depleted host, the expansion of endogenous, wild-type CD8 T cells was more reduced in the presence of IL-2-deficient donor CD8 T cells compared to IL-2-sufficient donor CD8s (Fig. 3c). This is in contrast to Fig. 4C, where the reduction is equivalent (here the antigen is non-infectious in nature).

CD8 T cells do produce IL-2 but its biological role was dismissed or ignored until now. After reading this articles, one question comes to my mind is if CD8 T cell can produce IL-2 and can express CD40L, why there is a need for CD4 T cell help?

David Usharauli        

Th17: thymus keeps it natural

IL-17-producing T cells, called T helper 17 cells (Th17) have been one of the main focus of immunological research since their discovery in 2006. Th17 cells gained such popularity for wrong reason: their involvement in bodies own tissue destruction or commonly known as autoimmune diseases. Very little is known about Th17 role in protection against infection (so far, we know that they contribute primarily in defense against fungi and extracellular bacteria). One peculiar feature of Th17 cells was the discovery that TGF-beta (in combination with IL-6 or IL-21) was needed for their generation, in in vitro assays, at least. This was interesting because TGF-beta is needed for the generation of Foxp3+ regulatory T cells (Tregs). According to current interpretation, the balance between Th17 and Tregs determines autoimmunity versus tolerance outcome.

If you are interesting to know more about Th17 cells, I will recommend reading the following paper recently published in Journal of Experimental Medicine. In this study (1), Kim et al, made several noteworthy observations: first, they showed that thymus from naive mice contains population of CD4 T cells expressing IL-17. Second, this thymic-derived Th17 cells are enriched in one particular T cell receptor gene, called V beta 3. Third, this Th17 cells need to interact with MHC class II molecules expressed on radioresistant thymic medullary epithelial cells to develop. Fourth, reduced T cell receptor signaling (Y145F mutation) favor their development. Fifth, the same Y145F mutation, however, prevented proper development/differentiation of peripheral, gut-associated Th17 cells.

It seems that paper represents the mix of two independent projects. However, the authors conclusions (and title of the paper) are mainly focused on results from only one project, namely, that (based on Y145F mutation) there are two, non-overlapping Th17 populations, one thymic-derived, called natural Th17 and another peripherally-converted.

David Usharauli

IL-6: one more time, please ?!

Chronic infections represent a special challenge to the adaptive immune system. It would not be an exaggeration to say that essentially what we know about how an adaptive immune system normally functions is entirely based on research or clinical observation related to the acute infections. Chronic infection develops in situations when adaptive immune system is not capable of complete or near complete elimination of invader-pathogen. In this scenario, invader-pathogen persists long-term, slowly spreading, infecting healthy cells. At this point adaptive immune system faces a difficult choice: if it kills all infected cells then the tissue and body will not survive because this will cause too much damage (so called immune pathology). Only alternative solution for adaptive immune system (to T and B cells) is to switch to the “damage-control” mode, where the focus will be containment, not elimination. This will require new pathway of effector differentiation that causes minimal damage to the infected tissues.

If you are interested to know what kind of modifications are happening to adaptive immune system during chronic infections, I recommend to read the following article recently published in Science (1). In this paper by James Harker et al, the focus is on the mouse model of chronic viral infection, specifically LCMV clone 13. The first (and in my opinion only) interesting observation they made was how IL-6 expression changes during clone 13 infection. Unlike acute infection, clone 13 produces two peaks of IL-6: early (at day 1-3) and late (at day 25). This late peak of IL-6 is primarily derived from irradiation-resistant follicular dendritic cells (FDCs). The authors do not go beyond this simple observation to explain how this is happening. Furthermore, for some reason, they are totally neglecting to discuss another cytokine, G-CSF that similar to IL-6 also had biphasic expression and may play independent role in protection during chronic infection. The rest of the article is mainly supporting data (more or less already known), for example, showing how IL-6 influences T follicular helper cell development, that in turn affects virus-specific antibody production level and its affinity (while earlier studies mainly ignored the role of B cells or antibodies played during LCMV infection, the more recent research clearly shows that at least for clone 13 infection antibody-dependent protection is essential (2).

Such prominent role of IL-6 in protection against chronic infection as this article shows is supported by other independent observation. For examples, an article published in Cell showed that IL-7, another cytokine, has protective effect during clone 13 infection and this effect was dependent on IL-6 (3).

David Usharauli