The start of my postdoc in late 1983 began a career-long interest in how B cells and T cells interact. A landmark study by Antonio Lanzavecchia in 1985 reinforced my passion for this subject, as it led to an important change in our understanding of cognate B cell−T cell communication.

The major paradigm of the early 1980s argued that T cells, previously activated by myeloid antigen-presenting cells (APCs), deliver lymphokines to B cells that are both necessary and sufficient for B cell activation. My own early experiments and others found instead that activated B cells both stimulated and were activated by T cells independently of lymphokines. To account for such MHC-restricted, antigen-specific B cell activation, additional models proposed that B cells and T cells interact through MHC−MHC contact, as well as by the T cell receptor (TCR) recognizing antigen bound to membrane immunoglobulin of the B cell. In this 'antigen bridge' model, B cells did not function as effective APCs.

he could separately block antigen uptake and presentation

The elegant paper by Antonio Lanzavecchia (Nature, 1985) made several fundamental advances that changed our understanding of B cell−T cell interactions. It was the culmination of multiple preceding studies from several laboratories that hinted at a new model. Lanzavecchia used antigen-specific B cell and T cell clones from single human donors. By briefly pulsing the B cells with antigen, washing them, then allowing antigen presentation to T cells, he could separately block antigen uptake and presentation, and so demonstrate that the two events are independent. His experiments showed that antigen uptake by B cells requires membrane immunoglobulin and concentrates soluble antigen; antigen presentation by B cells requires lysosomal processing and loading onto MHC molecules. The resulting B cell−T cell interactions result in both T cell activation, through MHC-restricted antigen presentation, and contact-mediated B cell activation. The study showed that B cells process and present MHC-bound antigen acquired through membrane immunoglobulin to the TCR, thereby functioning as classical APCs in cognate B cell−T cell communication rather than simply as an antigen bridge.

This study also raised important new questions about the role of membrane immunoglobulin as a B cell signalling receptor, and how antigen presentation by B cells regulates T cell activation and T cell-mediated B cell activation (see Further reading), processes that continue to occupy and fascinate immunologists today.