Linear ‘2–0–1’ lymphocyte development: hypotheses on cellular bases for immunity

It has been proposed that immune responses to intra- (type 1) and extra-cellular (type 2) pathogens are regulated by two T-cell subsets branching from type 0 cells on T-cell receptor (TCR) engagement and terminally differentiating in distinct cytokine environments. However, analysis at the single-cell level of human T cells and natural killer (NK) cells has revealed that peripheral immature cells of both lineages exist, produce only type 2 cytokines and either proliferate or differentiate to interferon-γ producing cells in distinct cytokine environments, even without TCR engagement. These data support the hypothesis that a modified balance between proliferation and/or survival and differentiation of immature type 2 cytokine-producing cells regulates productive, type 1, immune responses. This new concept provides a simpler and testable framework to understand and manipulate the immune system and immune pathologies.