Induction of type 2 activity in adult human CD8⁺ T cells by repeated stimulation and IL-4

Repeated administration or chronic presence of antigen during CD4⁺ T cell activation and a cytokine milieu enriched in IL-4 favour the generation and maintenance of a T_h2 population. However, there is little data on how these factors affect adult human CD8⁺ T cell functions. We established in vitro conditions to culture purified human CD8⁺ T cells, and investigated how repeated stimulation and exogenous IL-4 modulated their functions. Repeated TCR-CD3 stimulation of CD8⁺ T cells increased the number of CD25-, CD30- and CD40 ligand-expressing cells, and their capacity to secrete IL-4 and IL-5. In addition, repeatedly stimulated CD8⁺ T cells had cytotoxic activity and provided help to resting B cells for IgE synthesis. The presence of exogenous IL-4 during repeated stimulation further increased the number of CD25⁺ and CD30⁺ CD8⁺ T cells, up-regulated the number of IL-5⁺ cells, and increased IL-5 levels released. These observations demonstrate that repeated TCR-CD3 stimulation of normal human CD8⁺ T cells favoured the growth of cells with a type 2 phenotype and that this was further amplified by the presence of IL-4. These mechanisms may be important in virus-induced lung eosinophilic inflammation in healthy subjects and virus-induced exacerbations of asthma.