Inflammation modifies pattern of differentiation of commensal-specific T cells

1. #Commnesal S. epidermidis–specific -#MIIINA:H2-M3+ CD8+ T cells ordinarily differentiate into Tc1 or Tc17 subsets. However, when co-exposed to chitin or sand fly (source of #inflammation), Tc17 subset also produce type II cytokines. pic.twitter.com/g9Wy7BncPD

— David Usharauli (@3DiMMUNE) January 10, 2019

3. In any case, such deviation into type II cytokine+ lineage during co-exposure to S. epidermidis and inflammation is specific for CD8+CCR6+ cells (referred to as Tc17). pic.twitter.com/6uNCVHMtEz

— David Usharauli (@3DiMMUNE) January 10, 2019

5. The authors tried to show how skin #Treg deficiency could have the same effect on Tc17 de-differentiation. Again. the authors failed to show that IL-17+ and IL-5/IL-13+ Tc17 cells overlap. They don't. They put in suppl material these #data. Should be in main paper. pic.twitter.com/QupGc7HWLo

— David Usharauli (@3DiMMUNE) January 10, 2019

7. But again, no evidence is provided that IL-17+ T cells co-express IL-5 or IL-13 when exposed to IL-18. Exactly opposite. No overlap. pic.twitter.com/QG8U9EBSSH

— David Usharauli (@3DiMMUNE) January 10, 2019

So, what is my conclusions: this paper does not support the authors' conclusions about Tc17 acquiring Tc2 phenotype. Yes, it is true that RORgt+ or CCR6+ CD8+ T cells could acquire Tc2 phenotype but the same not true IL-17+ Tc17 cells or at least data are not there.

— David Usharauli (@3DiMMUNE) January 10, 2019

Reduced CTLA-4 signaling predisposes to Th2 driven gastric tumorigenesis

Anti-CTLA4 antibodies such as Yervoy, has been used in clinical practice to treat solid tumors. It supposed to work either by augmenting and revitalizing effector T cells function directly or indirectly through temporal silencing of inhibitory Foxp3+ Treg population or both. However, new study from Journal of Experimental Medicine showed that at least in [genetically predisposed] mice reduced CTLA-4 signaling by itself could cause Th2 driven tumorigenic transformation of stomach epithelial tissue.

For this study the authors created transgenic CTLA4 shRNA knockdown (CTLA4KD) mice on the BALB/c × C57BL/6 (B6) mixed genetic background. This they did because it appears that BALB/c but not B6 mice were susceptible developing gastric tumors in this model. CTLA4KD mice showed gastric epithelial transformation by 20w of age. Similarly, month long treatment of newborn BALB/c mice with anti-CTLA4 antibody also led to gastric epithelial transformation.

This tumorigenic transformation was CD4 T cell dependent and effector T cells from CTLA4KD but not from WT mice could mediate it. It indicated that changes in effector T cell composition and functionality were driving de novo inflammatory tumorigenesis.

Interestingly, gastric epithelial transformation were happening even in germ-free CTLA4KD mice lacking microbiota. However, since these mice also harbor increased numbers of inflammatory T cells, in all subsets analyzed such as Th1, Th2, Th17, and independent of microbiota it could indicate that T cells could be responding to antigens from food or environment.

Finally, elimination of canonical T helper cytokines showed that surprisingly neither IFN-γ nor IL-17 but IL-4 deficiency could abolish gastric epithelial transformation under conditions of reduced CTLA-4 activity.

In summary, this study suggests that inherited or clinically-induced reduction of CTLA-4 signaling in predisposed individuals could paradoxically lead to inflammatory tumorigenesis driven by type II immunity.

posted by David Usharauli

Bifurcation of type 2 immunity

Type II immunity is referred to a Th2 dominant immune response to a wide array of proteases, venoms and mechanical irritants. Both innate ILC2 cells as well as adaptive Th2 cells are involved in this process. The relationship between innate and adaptive components of type II immunity is still being defined.

A new study from Richard Locksley's lab published in Nature Immunology showed that priming of Th2 cells in the lymph nodes and their subsequent type II effector functions in the peripheral tissues could be bifurcated.

For example, the authors showed that parasitic nematode Nippostrongylus brasiliensis (Nb)-infected mice triple deficient in sensing of TSLP, IL-25 and IL-33, the epithelial cytokines which have been linked to Th2 cell function, have normal lymph node IL-4+ Th2 differentiation and IgE production, but significantly diminished potential to secrete IL-13 and IL-5, effector Th2 cytokines, in the periphery. 

Importantly, such bifurcation of Th2 effector functionality was T cell intrinsic by sensing locally produced "release" cytokines, TSLP, IL-25 and IL-33.

In summary, this study indicate that even at the level of Th2 cells their effector functionality could be bifurcated depending on the local tissue micro-environment. This concept is important to better understand how to treat different types of allergies, for example, IL-4/IgE dominant systemic allergies versus IL-5/IL-13 dominant local tissue chronic allergies.     

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