Runx3-dependent intraepithelial lymphocytes (CD4IELs) control gut tolerance to dietary antigens

Few days ago journal Science published another immunological study. This hard to read research paper showed that special subset of Foxp3–CD8αα+CD4+ intraepithelial lymphocytes (CD4IELs) found within intestinal epithelium play distinct and dominant role in preventing gut inflammation to dietary antigens.

It appears that induction or maintenance of Foxp3–CD8αα+CD4+ intraepithelial lymphocytes (CD4IELs) depends on antigens derived from either from gut flora [microbiome] or food.

The main finding of this paper was observation that antigen-specific T cell monoclonal mouse strain deficient for Foxp3 expression [but not Foxp3 wt] depleted of CD4IELs using anti-CD8α antibodies during antigen feeding showed severe intestinal inflammation and diarrhea. It suggests Foxp3–CD8αα+CD4+ intraepithelial lymphocytes (CD4IELs) play distinct and separate [that from Foxp3wt T cells] role in protecting intestinal tissue against antigenic inflammation.

Why is this paper relevant? For one, it indicates that tolerance to food antigens in physiological situations, for example during feeding, could be mediated by Foxp3–CD8αα+CD4+ intraepithelial lymphocytes (CD4IELs), and not by Foxp3+ CD4+ T cells, as scientists ordinarily assume. However, for now, we know relatively little about tissue-resident innate-like or adaptive-like cells, such as these Foxp3–CD8αα+CD4+ intraepithelial lymphocytes (CD4IELs).

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