Team tactics

Cooperation and coordination are the key to an effective type-2 immune response, but every team needs its captain. That's the conclusion of a study in Immunity by Fallon et al. Using compound cytokine-knockout mice, they have clarified the functional redundancy of the T helper 2 (T_H2) cytokines and confirmed that interleukin-4 (IL-4) is the 'David Beckham' of the 'T_H2 team'.

Previous analysis of cytokine-knockout mice has shown that deletion of a single gene often leads to no discernible phenotype. Furthermore, as IL-4 is crucial for the generation of T_H2 cells, its deletion also leads to the reduced expression of IL-5, IL-9 and IL-13 by T_H2 cells. Therefore, it is not possible to determine which functions are IL-4 specific and which are dependent on the other cytokines in a single IL-4-knockout animal. To resolve these issues, the authors created a panel of compound T_H2 cytokine-deficient mice, ranging from single to quadruple knockouts of IL-4, IL-5, IL-9 and IL-13. A first analysis of the immune function of these mice has been carried out in two in vivo models — intestinal challenge with the nematode parasite Nippostrongylus brasiliensis, which induces a T_H2 response, and a pulmonary granuloma model.

In the parasite model, Fallon et al. show that both IL-5 and IL-9 have a synergistic role in worm expulsion, but that even in the absence of the other T_H2 cytokines, IL-4 is effective. Eosinophilia and the goblet-cell response (mucus production) have been linked previously to IL-5 and IL-13, respectively, but these new studies show that IL-4 can independently induce both processes. Only when all four cytokines are absent does the immune response deviate to a T_H1 pattern.

In the T_H2 granuloma model, however, IL-4 alone was unable to induce the goblet-cell response, although IL-5-independent eosinophilia was still observed. In the absence of IL-5, IL-9 and IL-13, IL-4 was sufficiently potent to induce a T_H2 granuloma. By contrast, in a T_H1 granuloma model, knockout of all four cytokines enhanced the magnitude of granuloma formation, which demonstrates the reciprocal relationship between the T_H1 and T_H2 cytokines.

But, what is really interesting about these mice is the potential for future experiments. These mice offer a unique opportunity to study the T_H2 cytokines as an interdependent unit. Given the importance of the T_H2 response in human atopic diseases such as asthma, these mice will be a useful tool to investigate disease pathogenesis and design new therapies. Further experiments could help us to fully analyse the team tactics of the T_H2 response.