IL-2 instructs allergen-specific tissue resident memory TH2 cell development

IL-2 is one of the first cytokines [interleukins] discovered and we still have no clear idea of the extent of its involvement and role within immune system. One reason has to do with the fact that IL-2 "in vitro" and IL-2 "in vivo" behave if completely 2 different cytokines.

So, if I see new paper that could tell us more about IL-2, I can't resist reading it. This week journal Immunity has published one such article. There, the authors showed that IL-2 signaling via its high-affinity receptor IL-2α (also known as CD25) directed development of allergen-specific tissue resident memory TH2 cells. I will discuss only those data that are relevant and unequivocal for the story.

For this study, the authors used class II tetramers and i.v. labeling techniques to identify and track house dust mite (HDM) allergen-specific tissue resident T cells. They showed that primary allergen exposure generates lung tissue resident HDM-specific tetramer-positive CD4 T cells.

These lung tissue resident tetramer-positive CD4 T cells expressed IL-13 upon HDM re-challenge (that identified them as TH2 cells).

Next, using parabiont mouse model the authors showed that tetramer-positive CD4 T cells found in allergen challenged lung tissue were bona fide non-circulatory resident-memory TH2 cells.

Finally, using WT:CD25KO mixed bone marrow chimera mice the authors showed that development of lung tissue resident memory TH2 cells required IL-2 signaling via its high-affinity receptor IL-2α.

In summary, this study suggests that IL-2 signaling via its high-affinity receptor IL-2α is mandatory for resident-memory TH2 cell development. This is addition to already known IL-2 roles in Foxp3⁺ Treg and memory CD8 T cell development. From therapeutic point of view, this is one big mess.

David Usharauli

Steady-state IL-12p70-producing CD103+ DCs control magnitude of type II immunity

In my previous post I reviewed the role of microbiota and MyD88/TRIF pathway in CD103⁺ DC-derived TGF-β dependent IgA production. In the following review I will continue analyzing immunobiology of CD103⁺ DCs. Surprisingly, new paper published in JEM claims that CD103+ DCs naturally producing biologically active IL-12p70 restrain type II immunity during worm infection.

I have done some work on IL-12, so I was curious to review this paper. So lets begin. I will only show the data that I believe are relevant for the story. In first set of experiments, the authors showed that Batf3 ^-/- mice that lack CD103⁺ DCs have exaggerated type II response to S. mansoni eggs and worm infection itself (a typical Th2 trigger).

Similar exaggerated Th2 response were observed in Batf3 ^-/- mice infected with another Th2 trigger H. polygyrus. 

More importantly, Batf3 ^-/- mice showed increased resistance to H. polygyrus infection. 

To understand how Batf3-dependent CD103⁺ DCs influenced Th2 response, the authors analysed expression of IL-12, a cytokine known for its role in inhibiting Th2 response. Indeed, Batf3-dependent CD103⁺ DCs were main producers of steady-state IL-12 as measured by YFP expression under p40 promoter (p40 is a β chain of heterodimeric IL-12p70).

Finally, using bone marrow chimera, the authors showed that lack of biologically active IL-12 (IL-12p70) derived from Batf3-dependent CD103⁺ DCs was indeed responsible for exaggerated [and protective] Th2 response of Batf3^-/- mice to H. polygyrus.

Of note, in separate set of experiments with germ-free and MyD88/TRIF DKO mice, the authors claim that Batf3-dependent CD103⁺ DCs were producing biologically active IL-12p70 independently of microbiota or TLR signaling. However, in contrast to YFP expression, flow staining pattern with antibody against p40 revealed little staining of IL-12p40 in CD103⁺ DCs from any of the mice analyzed. So, if not the data with IL-12p35^-/-/Batf3^-/- BM chimera, I would have dismissed this whole study as an artifact (to be convincing the authors need to show these results with p40-YFP mice on GF and MyD88/TRIF background).

In summary, this study suggests that Batf3-dependent CD103⁺ DC-derived IL-12p70 influences magnitude of type II immunity.

David Usharauli

Microbiota drives airway IgA class switch via DC-derived TGF-β

IgA is a class of antibody specifically designed for protection and tolerance at mucosal surfaces. Since vast majority of antigens [both infectious or noninfectious nature] interact with mucosal tissues, knowledge of signals controlling IgA production would help to develop more robust vaccination protocols.

So I decided to review this paper from Journal of Experimental Medicine where the authors have analysed IgA promoting capacity of lung DCs.

Most experiments were done ex vivo on sorted DC and B cells. Most cultures included α-IgM and α-CD40 antibody to "mimic" T-dependent Ab production. First, the authors noticed that lung CD103⁺ and CD24⁺ DCs (but not CD64⁺ Mφ) could provide necessary signals to naive B cells to switch to IgA (similar to MLN DCs).

Next, the authors found that this IgA switch capacity of lung CD103⁺ and CD24⁺ DCs  were dependent of their ability to produce TGF-β and Retinoic Acid (Vitamin A metabolites).

Next, the authors found that microbiota influenced lung DCs capacity to drive IgA switch in naive B cells [though it is not clear whether it is airway or gut microbiota that does it].

Follow up experiments revealed that MyD88/TRIF signaling [most likely from microbiota] in lung DC cells increased TGF-β production and their IgA switch potential.

Finally, the authors showed that i.n (intra-nasal) or i.t. (intra-tracheal) immunization [but not s.c. immunization] with small dose of cholera toxin (CT) provided system-wide protection against cholera toxin re-challenge, implying body-wide re-distribution of airway primed CT-specific B cells.

In summary, this study showed the role of microbiota/MyD88/TGF-β/CD103⁺ DCs axis in driving airway mucosal IgA class switch.

David Usharauli