Summary We have developed a single-molecule imaging technique that uses quantum dot-labeled peptide-major histocompatibility complex (pMHC) ligands to study CD4+ T cell functional sensitivity. We found that naive T cells, T cell blasts and memory T cells could all be triggered by a single pMHC to secrete tumor necrosis factor-α (TNF-α) and interleukin-2 (IL-2) cytokines with a rate of ~1,000, ~10,000 and ~10,000 molecules/min respectively and that additional pMHCs did not augment secretion, indicating a digital response pattern. We also found that a single pMHC localized to the immunological synapse induced the slow formation of a long-lasting T cell receptor (TCR) cluster, consistent with a serial engagement mechanism. These data show that scaling up CD4+ T cell cytokine responses involves increasingly efficient T cell recruitment rather than greater cytokine production per cell.

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Summary γδ T cells contribute uniquely to host immune defense. However, how they function remains an enigma. Although it is unclear what most γδ T cells recognize, common dogma asserts that they recognize self-antigens. While they are the major initial Interleukin-17 (IL-17) producers in infections, it is unclear what is required to trigger these cells to act. Here, we report that a noted B cell antigen, the algae protein-phycoerythrin (PE) is an antigen for murine and human γδ T cells. PE also stained specific bovine γδ T cells. Employing this specificity, we demonstrated that antigen recognition, but not extensive clonal expansion, was required to activate naïve γδ T cells to make IL-17. In this activated state, γδ T cells gained the ability to respond to cytokine signals that perpetuated the IL-17 production. These results underscore the adaptability of lymphocyte antigen receptors and suggest a previously unrecognized antigen-driven rapid response in protective immunity prior to the maturation of classical adaptive immunity.

γδ T cells are the major initial IL-17 producers in acute infections. Recent studies indicate that some γδ T cells have IL-17 producing capabilities without explicit induction of an immune response. They are preferentially localized in barrier tissues and are likely to originate from fetal γδ thymocytes. In addition, γδ T cells present in the secondary lymphoid organs will mature and differentiate to produce IL-17 after antigen encounter in an immune response. Based on these studies we propose that there are two different sets of IL-17 producing γδ T cells (Tγδ17) referred to as the “natural” and the “inducible” Tγδ17 cells. This review focuses on recent publications leading to the delineation of these two types of cells and their implied roles in host immune defense.