A Three‐cell Model for Activation of Naïve T Helper Cells

It is generally assumed that the activation of naïve T helper (Th) cells is the result of a two-cell interaction between the Th cell and a dendritic cell (DC) and that three signals are required. Signal one or stimulation is the recognition by the T-cell receptor (TCR) of antigenic peptides presented by major histocompatibility complex (MHC) class II molecules. Signal two or co-stimulation is mainly provided by the triggering of CD28 on the T cell by CD80 and CD86 molecules on the DC. Signal three or polarization directs T-cell differentiation into various effector phenotypes such as Th1 and Th2. Both signals, two and three, are often assumed to result from the binding of microbial products or endogenous molecular danger signals to germline-encoded receptors such as toll-like receptors (TLR) on the DC. However, recent data challenge this two-cell model by revealing that Th1 polarization requires the presence of interferon-gamma (IFN-gamma) provided by a third cell. I propose here a three-cell model for naïve Th-cell activation. In this model, delivery of signal three by the DC is dependent on help provided by other innate immune cells such as NK cells, NK T cells, gammadelta T cells, mast cells, eosinophils and basophils. The rationale behind this model is that the innate immune system has been designed by evolution to select an appropriate class of immune response to protect the host.