TYRO3-PROS1 axis is a novel inhibitory circuit for type II immunity

This week Science published very simple and concise study showing that in mice DC-specific TYRO3 [TAM] receptor tyrosine kinase, and T_H2 cell-specific TAM receptor agonist PROS1, represent novel inhibitory circuit dampening type II immunity (allergy, asthma, atopic dermatitis).

The senior author for this study, Carla V. Rothlin (department of immunobiology, School of Medicine, Yale University) is a shareholder of Kolltan Pharmaceuticals, so we may see some of these data going into biotech drug design. 

Using a house dust mite (HDM) model of allergic airway inflammation, the authors showed that Tyro3^–/– mice showed exaggerated allergic (T_H2) response.

Next, the authors showed that PDL2⁺ CD11c⁺ DCs expressed Tyro3 and that Tyro3^–/– PDL2⁺ DCs were the main drivers of exaggerated T_H2 cell response.

Finally, mice lacking CD4 T cell-specific PROS1 expression (Tyro3 agonist ligand) displayed similar exaggerated T_H2 cell response to the helminth N. brasiliensis ( T_H2 activator).

In summary, this study revealed that Tyro3-PROS1 axis represents novel inhibitory circuit specifically involved in regulating type II immune response (but not in T_H1 or T_H17 responses) and it could be targeted therapeutically (though it is not clear whether Tyro3-PROS1 axis also functions in humans. Limited data about human cells provided by the authors in the article were not conclusive).

David Usharauli

Enigmatic tuft cells residing in intestine constitutively produce type II immunity primer cytokine IL-25

Type II immunity is responsible for such physiological and pathological conditions as allergy, anti-parasite [anti-worm] expulsion response, thermoregulation and lean body metabolism. Right now our therapeutic toolkit to influence this system is minimal or even nonexistent. We just don't know enough about it [unlike TH1 response].

This new paper in journal Nature is a good example for this scientific gap in type II immunity. Here, the authors, led by Richard Locksley at UCSF, revealed that little known tuft cells residing in intestine contribute to type II immunity by secreting IL-25.

It appears that within intestine we have 5 cell types, 1 absorptive enterocytes, and 4 secretory cell types: paneth, tuft, goblet and enteroendocrine. By using Flare25 mouse knock-in/deleter model, the authors found that in normal mouse intestine, IL-25 was expressed by rare cells that were also positive for EpCam⁺ and doublecortin like kinase 1 (DCLK1⁺). These were markers for tuft cells (EpCam⁺ DCLK1⁺) [IL-25⁺cells were negative (a) for chromogranin A, a marker for enteroendocrine cells, (b) lysozyme, a marker for paneth cells, and (c) mucin 2, a marker for goblet cells].

Next, the authors showed that tuft cells undergo expansion following worm challenge (type II immune response) in a IL-13-dependent manner (produced by group 2 innate lymphoid cells ILC2).

IL-13 producing intestinal ILC2 were in turn supported by IL-25⁺ producing tuft cells in a forward-feed circuit.

Physiological significance of IL-25⁺ tuft cells became evident when the authors showed delay in anti-worm expulsion response in mouse model of epithelial [tuft]-selective deficiency of IL-25 production.

In summary, this study uncovered immunological role of tuft cells in type II immunity. Naturally occurring tuft cell-derived IL-25 support development and maintenance of naturally occurring IL-13⁺ ILC2 and vise versa.

David Usharauli

Microbiota connects type II immune system to lean body metabolism

There is a renewed interest in gut microbiota research. Initially, this revival of microbiota studies came from observations that obese and lean people have different gut microbiota. It is not clear how exactly microbiota modulates energy metabolism and the research is ongoing in this direction.

For example, journal Nature Medicine has just published another paper where the authors showed that microbiota modulates energy metabolism through its action on a specialized adipose tissue called brown [beige] adipose tissue.

A peculiar aspect of this study [and main reason why it was published in this journal in the first place] has to do with sophisticated methodologies the authors used to study energy metabolism in mice (such as glucose uptake assays with 2-[¹⁴C]-deoxyglucose, [¹⁸F]fluorodeoxyglucose, 2-[1-³H]deoxyglucose, micro-PET-CT, etc).

Basically, the authors showed that when mice are treated with broad spectrum antibiotics, inguinal subcutaneous and perigonadal visceral adipocytes undergo modification (browning and cell size reduction) resembling adipose tissue in Germ-free mice.

Antibiotic treatment led to the increase in Ucp-1⁺ cells in inguinal adipose tissue confirming "browning" of adipose tissue.

In addition, the authors observed "browning" of inguinal and perigonadal adipose tissues in antibiotic treated mice even at thermoneutral conditions (at 30℃ for mice).

Next, the authors showed that microbiota depletion improved "lean body" metabolism both in obese-prone [ob/ob] and high-fat diet fed [HFD] mice.

Finally, the authors showed that antibiotic treatment was associated with type II cytokine profile in "browning" inguinal adipose tissue, including presence of tyrosine hydroxylase (TH) expressing M2 MΦ.

In summary, these results [re]confirmed that microbiota played an important role in "lean body" metabolism associated with development of "brown" adipose tissue. Interestingly, two pathways known for brown adipose tissue development [exposure to low temperature and microbiota depletion] required type II immune system. Type II immune system is mostly known for its involvement in allergy and more recently tyrosine hydroxylase (TH) expressing M2 MΦ has been implicated in neuro-inflammation. It remains to be discovered whether "lean body" metabolism and allergy are interconnected or whether they represent two independent outcome of type II immunity 

David Usharauli

Tissue-specific regulatory T cells control asthma development

Foxp3+ CD4 regulatory T cells (T regs) maintain immune tolerance to self. Exactly how do they do it, no one really knows. Studies have described so many different mechanisms of T regs function that one can only wonder whether these cells really belong to one family.

Most likely, T regs may function in a tissue-specific manner as proposed by P. Matzinger and T. Kamala. New study published in Nature Immunology may support this hypothesis.

This study is a combined effort by French and German scientists. Here, the authors have examined the role of protein kinases in T regs function. Initial experiments showed that protein kinase, CK2 (casein kinase 2), was the most up-regulated kinase in activated T regs compared to effector T cells.

Next, the authors generated a mouse model carrying Foxp3-specific deletion of CK2 in T regs by crossing Foxp3-cre mice with CK2 fl/fl mice. 

Interestingly, analysis of different tissues in Foxp3-cre CK2  fl/fl mice revealed that only lung tissue was affected by Foxp3-specific CK2 deletion in T regs.

Further analyses revealed that Foxp3-specific deletion of CK2 in T regs resulted in selective increase in type 2 immune signature in lung draining lymph nodes and in serum.

In fact, spontaneous lung inflammation in naive Foxp3-cre CK2  fl/fl mice was comparable to allergic lung inflammation (asthma) in antigen sensitized control mice.

However, surprisingly, T regs homing into lung tissue was not affected by Foxp3-specific CK2 deletion in T regs. More detailed analysis of T regs from Foxp3-cre CK2  fl/fl mice revealed selective up-regulation of inhibitory receptor ILT3.

The authors showed that ILT3 expression in CK2-deficient T regs could dampen TCR signalling in T regs.

Finally, the authors showed that CK2 deletion in T regs led to selective increase in numbers of type 2 response promoting IRF4+ PD-L2+ dendritic cells (DCs).

In summary, these results indicate that CK2 deletion in T regs induces ILT3 up-regulation and attenuation of TCR signaling in lung-tissue T regs, leading IRF4+ PD-L2+ dendritic cells (DCs) expansion and type II inflammation in the lung. 

How these results advance our knowledge in Foxp3+ T cells? No data are provided to explain why lung-tissue T regs were so selectively affected by CK2 deletion or how IRF4+ PD-L2+ DCs are amplified. Very interesting and very strange.

Let me know what do you think about this study.

David Usharauli