It is now well accepted that CD4+ T cells come in different flavours, including: T helper 1 (TH1) cells that produce interferon-γ (IFNγ) and are involved in responses to intracellular pathogens; TH2 cells that produce interleukin-4 (IL-4), IL-5 and IL-13, and respond to helminth infections; and TH17 cells that produce IL-17A and IL-17F, and deal with extracellular pathogens. This division of labour has led to specific CD4+ T cell subsets being associated with specific diseases (autoimmunity for TH1 and TH17 cells, and allergic responses for TH2 cells). However, ∼30 years ago, this level of complexity was only beginning to be appreciated, as documented in a landmark study by Robert Coffman and colleagues (Mossmann et al., 1986).

there was diversity within the CD4+ T cell pool, but the underlying mechanisms remained obscure

Beginning in the late 1970s, initial studies in mice had suggested that there were subsets of L3T4+Lyt2− (CD4+CD8−) T cells with different activities (Tada et al., 1978; and Kim et al., 1985). These groups, as well as others, showed that there were T cell populations that provided different forms of help in antibody responses. These studies suggested that there was diversity within the CD4+ T cell pool, but the underlying mechanisms remained obscure.

This changed in 1986, when Mossmann et al. used T cell clones to show that there were two distinct subsets of T helper cells. Using the nomenclature of Tada et al., they referred to these subsets as TH1 cells (producing IFNγ, IL-2 and lymphotoxin) and TH2 cells (producing BSF1 and TCGF2 (now both known as IL-4), and MCGF2 (now both known as IL-5)). The TH2 cell clones could also induce the expression of Ia antigens on B cells and enhance IgG1 and IgE synthesis. Importantly, IFNγ was capable of inhibiting both of these TH2 cell activities, which showed that the subsets cross-regulated each other.

The remarkable aspect of this work was that it was carried out at a time before enzyme-linked immunosorbent assays, cytokine-specific antibodies, intracellular flow cytometry and quantitative PCR. The T helper cell clones were characterized using bioassays for the activities they produced. This work pioneered subsequent analysis of CD4+ T cell differentiation and represented a paradigm shift in how immune responses are assessed and studied.