IRA B cells: going beyond IgM defense line

B cells produce antibodies that clear pathogen from body tissues and protect against re-infection. In general, there are two types of B cells. One type, called innate-like, produce Ab when stimulated by bacterial ligands alone (for example, LPS). 2^nd type of B cell require additional T cell-derived signals to produce Ab. While T-dependent Ab production is well-described, little is known about innate-like B cells, their function or contribution to the protection against pathogens.

If you are interested to know more about innate-like B cells, I will recommend reading new paper published in Science. In this study (1) by Rauch, Chudnovskiy, Robbins et al, the authors made surprising observation that in response peritoneal injection of TLR4 ligand, LPS, the predominant cell population in the spleen producing granulocyte-macrophage colony-stimulating factor (GM-CSF) were B cells (Fig 1). The authors dubbed these cells innate response activator (IRA) B cells. The phenotype of IRA B cells producing GM-CSF showed that they were derived from innate-like B cells, also known as B1a cells (Fig 2B). The authors showed that direct signaling through TLR in B1a cells was necessary to develop into IRA B cells (Fig. 3E). By creating mixed chimera where only B cell were deficient in producing GM-CSF, the authors showed that absence of IRA B cells compromised bacterial clearance from the blood (Fig. 4I) in mouse model of peritonitis (sepsis model) and reduced survival rate compared to control [0 vs. 40% survival 72h post peritonitis onset] (Fig 4B).

It has been known for some time that B1a cells from peritoneal cavity migrate into spleen upon activation. Until now, the thinking was that they differentiate into plasma cells producing poly-reactive innate IgM. However, this is a first report to show that besides IgM production, IRA B cells carry another important message, namely GM-CSF, that may influence other cells (macrophages, DCs, neutrophils) to participate in response against pathogens. However, at this stage, it is not clear how exactly IRA B cell-derived GM-CSF has such a protective effect.

David

1. http://www.sciencemag.org/content/335/6068/597.abstract

P.S. Analogous observation regarding B cells was recently described in Nature. There (2), the authors showed that iNOS/TNF-alpha producing B cells in the gut play a protective role during immune response to C. rodentium.

2. http://www.nature.com/nature/journal/v481/n7380/full/nature10698.html

Langerhans scapegoats

Langerhans cells (LCs) residing in the epidermal layer of the skin represent a specialized dendritic cell subset. However, what is exactly their function is still a mystery. Even the development of mouse models specifically lacking LCs could not resolve the controversy. The new paper published in Science make this case even more confusing.

The study by Modi BG and Neustadter J, et al. (1), examined chemically-induced carcinogenesis model in mice lacking LCs. This particular mouse model lacks Langerhans cells due to langerin-driven diphtheria toxin A expression (langerin-DTA mouse). Any cells that will express langerin will be eliminated from the body. Because Langerhans cells express langerin they will be constitutively depleted. The authors showed that this mice were resistant to DMBA-TPA (carcinogens) induced skin papilloma development. Interestingly, this mice were resistant to DBMA-TPA induced papillomas even in absence of T cells. The authors showed that one way Langerhans cells were contributing to the papilloma development was through metabolism of DBMA into active DBMA-t-3, 4 diols. DBMA-t-3, 4 diol, in turn, had a mutagenic effect on keratinocyte DNA leading to papillomas. This mechanism was supported by observations that (a) Langerhans cells express enzymes capable of metabolizing DBMA and (b) application of DBMA-t-3, 4 diols induced papilloma development even in langerin-DTA mice (though direct application of DBMA-t-3, 4 diol induced low number of papillomas compared to DBMA). This may suggest that simple metabolism of DBMA into DBMA-t-3, 4 diol by Langerhans cells is not only mechanism by which Langerhans cells participate in tumorogenesis. In this regard, it is useful to keep in mind that Langerhans cells residence (maintenance) in skin is critically depended on the action of tumor-growth factor-β (TGF-β). It would be interesting to examine how absence of Langerhans cells affects the role of TGF-β in DBMA-TPA induced papilloma development.

David

1. http://www.sciencemag.org/content/335/6064/104.short

Too good to be to true

Currently, Foxp3+ CD4 T cells, also known as regulatory T cells (Tregs), are most studied and still least understood T cell subset. Why is that? The main challenge to Tregs/suppressor concept is that they do not fit in any mainstream theoretical framework of immune system organization. In absence of such working model, translation of basic Tregs research into clinical practice will look as sporadic efforts with no real progress and consensus.

If you are interesting to know more about Tregs, I will recommend reading following article published in journal Nature few weeks ago. This study by Michael Rosenblum et al. (1), exactly represents that confusion typical to Tregs research. First, this is a fairly simple study and we may applaud Nature for taking step to publish a research paper that does not include highly expensive (in many cases completely irrelevant or useless) experimental methods. Actually I see some pattern in this direction from Nature's editorial board. Nature started to publish simple papers (the most recent example of this kind is a research article about dendritic cells and lymph node-specific high endothelial venules). However, simplicity is not the same as significance or relevance.

In this new article by Michael Rosenblum et al., the authors created mice that will express OVA antigen in the skin only upon treatment with a doxycycline and crossed them to the mice transgenic for OVA-specific T cell. In absence of doxycycline, this modified mice have healthy skin, and harbor substantial population of OVA-specific Tregs (due to doxycycline-independent thymic expression of OVA). Within 5-10 days upon doxycycline treatment, the skin becomes highly inflamed due to OVA-specific T cell effector infiltration. However, within 40-60 days skin inflammation is completely resolved. How? The authors suggested that it has to do with Tregs, because Tregs depletion led to more severe skin inflammation. The problem is that even in condition of Tregs depletion, the skin inflammation is still resolved and almost within the same time frame as in presence of Tregs (Fig 2a, e, g). In general, Tregs depletion with anti-CD25 antibody may not eliminate all Tregs, so this particular experiments are not optimal approaches. This leave open the main question what is the role of Tregs in this process. In Fig. 4E, f, the authors showed that when expression of OVA is turned off for 20-30 days and then turned on again, skin inflammation that developed 2^nd time is less severe and is resolved at faster rate compared to initial skin inflammation in the same mice. The authors showed that after resolution of initial skin inflammation, there were more Tregs retained in the skin and these Tregs were more potent in suppressing naïve T cells proliferation. The authors conclusion is that tissue (skin) maintains memory Tregs specific to initial antigen and their presence is required to resolve skin inflammation.

Essentially, the authors idea is that similar to effector T cells, Tregs also undergo the same phases of a typical immune response: activation, expansion, memory differentiation. In my opinion, the data to support this claim are weak. First, Tregs depletion should have been done with Foxp3-DTR mice to selectively deplete Foxp3+ T cells and second, no data is provided to show that initial OVA expression and inflammation does not select for skin epithelial cells expressing less of OVA that may have explained reduced inflammation upon re-expression of OVA in the skin.

David

1. http://www.nature.com/nature/journal/vaop/ncurrent/full/nature10664.html