IL-17-producing cells go it alone

Two recent reports in Nature Immunology identify interleukin-17 (IL-17)-producing cells as a unique T helper (T_H)-cell lineage with developmental requirements that are distinct from those of T_H1 and T_H2 cells.

IL-23-dependent, IL-17-producing CD4⁺ T cells are associated with autoimmunity. However, it is not clear whether these cells differentiate along a pathway that is distinct from those pathways that give rise to T_H1 and T_H2 cells or whether they are derived from a T_H1-cell intermediate. Both groups set out to address this issue and found that, when naive CD4⁺ T cells were stimulated in vitro through their T-cell receptor (TCR) in the presence of IL-23, few cells produced IL-17, but a substantial proportion produced interferon-γ (IFN-γ). However, if IFN-γ-specific antibody was also included in the culture then a large population of IL-17-producing cells emerged. A further increase in the proportion of IL-17-producing CD4⁺ T cells was observed if IL-4-specific antibody was also added to the culture, indicating that IFN-γ and IL-4 independently inhibit the generation of IL-17-producing cells.

Harrington et al. further investigated the factors that are required for the development of IL-17-producing cells in vitro. They found that naive CD4⁺ T cells isolated from mice that were deficient in signal transducer and activator of transcription 1 (STAT1), STAT4 or T-bet (factors that are required for differentiation into T_H1 cells) were not impaired in their ability to differentiate into IL-17-producing cells when stimulated through their TCR in the presence of IL-23. Similarly, the development of IL-17-producing cells was not impaired when the stimulated naive CD4⁺ T cells were isolated from mice that were deficient in STAT6, which promotes differentiation into T_H2 cells.

Park et al. generated similar data in vivo: they found that the generation of IL-17-producing CD4⁺ T cells following immunization with antigen and complete Freund's adjuvant (CFA) was not impaired in mice that were deficient in STAT4, STAT6 or T-bet. However, the generation of IL-17-producing CD4⁺ T cells following immunization with antigen and CFA was impaired in mice that were deficient in CD80 and CD86 and in mice that were deficient in inducible T-cell co-stimulator (ICOS), indicating that CD28 and ICOS are required for the development of these cells.

These studies clearly define IL-17-producing CD4⁺ T cells as a unique subset of T_H cells that develop along a pathway that is distinct from the T_H1- and T_H2-cell differentiation pathways. Given the clear pathogenic effects of IL-17-producing CD4⁺ T cells in autoimmune disease, both groups suggest that upsetting the balance of IFN-γ and IL-4 could be a contributing factor to autoimmunity.