Production of Abs against protein Ags usually requires collaboration between T and B cells. Before the publication of the articles featured as this month’s Pillars of Immunology, studies using small organic molecules (haptens) to modify proteins demonstrated that only preparations of Ag that provided both this chemical modifier, the hapten itself, as well as the carrier to which such haptens are commonly attached elicited high-titer antisera. Avrion Mitchison, Klaus Rajewsky, and their colleagues (1, 2) established the involvement of B cells in hapten recognition and that of T cells in recognizing the carrier as a means to provide assistance to the hapten-specific B cells. It was also found that the hapten and carrier had to be physically linked to elicit the required response.

Absent any detailed understanding of the structure of Ag-specific receptors on T cells, proposals for how T-B collaboration might come about included an Ag bridge via which the B cell and T cell, using Ag-specific receptors, could each recognize the same Ag. This notion fell by the wayside with the discovery by Unanue and his colleagues that T cell activation did not require intact Ag but instead involved fragments of Ag (3, 4). Their groundbreaking work led to the concept of Ag processing: the conversion of an intact Ag into an entity that could be interpreted by Ag-specific T cells. The small size of Ag fragments capable of providing information to T cells severely constrained any models that invoked a direct Ag bridge between the B and T cells.

With the discovery of MHC restriction, it became clear that T cells inspect the cells with which they interact through the lens of the MHC products that present these Ag fragments to the T cell in the form of MHC-peptide complexes. Two landmark papers, highlighted here as Pillars of Immunology, provide the conceptual link between Ag-specific recognition by B lymphocytes and the provision of Ag-specific T cell help to Ag-experienced B cells.

Rock et al. (5, 6, 7) isolated B cells specific for the hapten 2,4,6-trinitrophenyl (TNP)2 on Ag-coated dishes. These B cells, exposed to a TNP-conjugated carrier, presented the carrier-derived epitopes to carrier-specific, class II MHC-restricted T cells 1000-fold more efficiently than did TNP-specific B cells exposed to an unmodified carrier. Subsequent experiments using two different haptens and two different carriers showed that hapten recognition was a property conferred by B cells and that carrier recognition was the domain of T cells.

Working independently on Ag presentation by human B cells, Lanzavecchia (8) reached conclusions that were both qualitatively and quantitatively remarkably similar to what was found in the mouse model. Lanzavecchia isolated T cell clones specific for tetanus toxoid and used these as responders to tetanus toxoid-specific B lymphoblastoid cell lines obtained by EBV transformation. In this model, the possession of Ag-specific receptors rendered the B cells vastly superior in their ability to present Ag to tetanus toxoid-specific T cells. Lanzavecchia’s experiments further allowed the demonstration that these interactions were MHC restricted and established the conceptual similarity with the observations made for mouse B and T cells.

The experiments reported by Rock et al. and Lanzavecchia provided the framework for the understanding of how the linked recognition of hapten and carrier can determine the ensuing Ab response, where hapten is now referred to as the B cell epitope and the carrier determinants as T cell epitopes. Much of what we currently know about Ag presentation via class II MHC-restricted pathways is based on these landmark observations. The ability of a surface Ig to capture its cognate Ag, coupled to receptor-mediated endocytosis and endo-lysosomal processing, leads to the generation of the pool of peptides from which the class II MHC products lying in wait in endosomes must choose. The peptides that bind to class II MHC products are then ferried to the surface, ready for inspection by T cells specific for these peptide-MHC complexes. It would not be a stretch to state that the ensuing research emphasis on class II trafficking and the conversion of protein Ags into ligands for class II MHC products owes as much of a debt to these two papers as to the independent exploration of phagocytic cells, and later dendritic cells, as APCs.

The interested reader not involved in the field of Ag processing at that time would do well to also read the commentary of Jonathan Howard (9) that accompanied the publication of these two papers; it provides an insightful discussion of the historical precedents to these papers and in a remarkably prescient manner frames the questions that have shaped the field since their publication.

2

Abbreviation used in this paper: TNP, 2,4,6-trinitrophenyl.

1
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