Wednesday, September 2, 2015

Adaptive Th2 cells can double as innate cells during allergy and helminth infection

Antigen specificity is a dominant feature of adaptive immune system. However, on occasions, fully differentiated effector T cells do show TCR-independent responsiveness to cytokines. Whether this is a good or bad thing is not easy to tell. 

For this study the authors had used a dual-reporter mouse model, called 4C13R, where both cytokine IL-4 and IL-13 are genetically labeled. Initially, the authors showed that adoptively transferred in vitro differentiated Th2 OT-II transgenic T cells, on 4C13R background, could secrete IL-13 (but not IL-4) in response to cytokine IL-33 (in combination with STAT5 activator IL-7 or TSLP).

Similarly, the authors observed TCR-independent IL-13 secretion by in vivo differentiated Th2 OT-II 4C13R cells to a Papain challenge (Papain is a protease and has been shown to induce type II immune response).

This TCR-independent secretion of IL-13 by differentiated Th2 cells was driven by IL-33.

Since type 2 innate lymphoid cells (ILC2) are known to respond to IL-33, the authors analyzed secretion of IL-13 by both Th2 and ILC cells after Papain challenge (here, mice were initially exposed to N. brasiliensis, a type II activator helminth). Both population could respond to Papain by secreting IL-13 (but not IL-4).

Similar results were obtained with another allergen, house dust mite extract (HDM).

Further experiments with RAG2-IL-2Rγ DKO hosts, which lack endogenous T and ILC2 cells, revealed that adoptive transfer of in vitro differentiated Th2 cells was sufficient to induce eosinophilia in lung tissue upon HDM exposure (allergen exposure).

The authors reasoned that in physiological situations initial antigenic priming would increase the number of Th2 cells to the level comparable to that of ILC2 and this would play a significant role in host protection or response to type II irritants (worm or allergen). Indeed, the authors showed that Th2 cells developed after first helminth infection could provide partial host protection to a second helminth infection, even in absence of ILC2 cells (in RORα bone marrow chimera).

In summary, these results suggest that adaptive immune cells can take the function of innate cells when necessary. Here, IL-13 appears to be a dominant cytokine that drives type II immune effector function (in 1990s ad early 2000s, the prevalent hypothesis positioned IL-4 in the center of type II immune effector response).

Such TCR-independent responsiveness has important implications for treatments of type II immune disorders such as allergy or dermatitis. For example, antigen (TCR ligand) desensitization protocol for allergy treatment may not provide full protection against allergic reaction due to IL-13 secretion (since it can be secreted independent of TCR signaling). On the other hand, blockade of IL-13 and IL-33 signaling may represent clinically relevant therapy (alone or in combination with antigen desensitization).  

David Usharauli

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