Functional heterogeneity of human memory CD4+ T cell clones primed by pathogens or vaccines

For T cells, variety is the spice of life CD4+ helper T cells come in a variety of flavors. This allows them to respond in a manner that is tailored to the pathogen they encounter. Becattini et al. wondered whether multiple “flavors” of human CD4+ T cells respond to specific stimuli or if just one flavor dominates. To find out, they stimulated human memory CD4+ T cells with a fungus, a bacteria, or a vaccine antigen. Multiple helper cell subsets participated in each response. T cell receptor sequencing revealed that in some cases, T cells with the same specificity acquired different helper cell fates. Thus, there is more heterogeneity in human T cell responses than previously appreciated. Science, this issue p. 400 Human memory CD4+ T cells acquire multiple fates when responding to infection or vaccination. [Also see Perspective by Davis] Distinct types of CD4+ T cells protect the host against different classes of pathogens. However, it is unclear whether a given pathogen induces a single type of polarized T cell. By combining antigenic stimulation and T cell receptor deep sequencing, we found that human pathogen- and vaccine-specific T helper 1 (TH1), TH2, and TH17 memory cells have different frequencies but comparable diversity and comprise not only clones polarized toward a single fate, but also clones whose progeny have acquired multiple fates. Single naïve T cells primed by a pathogen in vitro could also give rise to multiple fates. Our results unravel an unexpected degree of interclonal and intraclonal functional heterogeneity of the human T cell response and suggest that polarized responses result from preferential expansion rather than priming.