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         

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