1) Induction of humoral antibody formation involves the obligatory recognition of two determinants on an antigen, one by the receptor antibody of the antigen-sensitive cell and the other by carrier antibody (associative interaction). 2) Paralysis of antibody formation involves the obligatory recognition of only one determinant by the receptor antibody of the antigen-sensitive cell; that is, a nonimmunogenic molecule (a hapten) can paralyze antigen-sensitive cells. 3) There is competition between paralysis and induction at the level of the antigen-sensitive cell. 4) The mechanisms of low- and high-zone paralysis, and maintenance of the unresponsive state, are identical. 5) High-zone paralysis occurs when both the carrier antibody and the receptor antibody are saturated, so that associated interactions cannot take place. 6) The mechanisms of paralysis and induction for the carrier-antigen-sensitive cell are identical to those for the humoral-antigen-sensitive cell. 7) The formation of carrier-antigen-sensitive cells is thymus-dependent, whereas humoral-antigen-sensitive cells are derived from bone marrow. Since carrier antibody is required for induction, all antigens are thymus-dependent. 8) The interaction of antigen with the receptor antibody on an antigen-sensitive cell results in a conformational change in an invariant region of the receptor and consequently paralyzes the cell. As the receptor is probably identical to the induced antibody, all antibody molecules are expected to be able to undergo a conformational change on binding a hapten. The obligatory associated recognition by way of carrier antibody (inductive signal) involves a conformational change in the carrier antibody, leading to a second signal to the antigen-sensitive cell. 9) The foregoing requirements provide an explanation for self-nonself discrimination. Tolerance to self-antigens involves a specific deletion in the activity of both the humoral- and the carrier-antigen-sensitive cells.

https://science.sciencemag.org/content/sci/169/3950/1042.full.pdf

A Theory of Self- Nonself Discrimination.

It is well known that B cells require T-cell help to produce specific antibody. Classic experiments suggested that antigen-specific helper T cells interact with antigen-specific B cells via an antigen 'bridge', the B cells binding to one determinant on an antigen molecule (the 'hapten'), while the T cells at the same time recognize another determinant (the 'carrier'). T-helper cells bind specifically to antigen-presenting cells (APC), which have picked up and processed the appropriate antigen, and this interaction, like the interaction of T-helper cells with specific B cells, is restricted by products encoded by the major histocompatibility complex (MHC). Whereas conventional APC such as macrophages display no binding specificity for antigen, B cells have clonally distributed antigen-specific surface immunoglobulin receptors which would be expected to enhance their capacity to present antigen to T cells. These findings are difficult to reconcile with the simple 'antigen bridge' mechanism of interaction, because it is hard to visualize how the bimolecular complex (processed antigen plus MHC molecule) on the APC surface can resemble the trimolecular complex (antigen bound to surface immunoglobulin plus MHC molecule) on the B-cell surface. To address this problem, we have cloned and immortalized human antigen-specific B cells with Epstein-Barr virus (EBV) and analysed their interaction with T-cell clones specific for the same antigen. We report here that surface immunoglobulin is indeed involved in the uptake and concentration of antigen, allowing specific B cells to present antigen to T cells with very high efficiency. However, the antigen must first be internalized and processed by specific B cells and it is then presented to T cells in an MHC-restricted manner indistinguishable from that characteristic of conventional APC.

Antigen-specific interaction between T and B cells

https://www.med.nyu.edu/skirball-lab/dustinlab/pdfs/victoria_2010.pdf

Germinal center dynamics revealed by multiphoton microscopy with a photoactivatable fluorescent reporter.

▪ Abstract Helper T (Th) cell–regulated B cell immunity progresses in an ordered cascade of cellular development that culminates in the production of antigen-specific memory B cells. The recognition of peptide MHC class II complexes on activated antigen-presenting cells is critical for effective Th cell selection, clonal expansion, and effector Th cell function development (Phase I). Cognate effector Th cell–B cell interactions then promote the development of either short-lived plasma cells (PCs) or germinal centers (GCs) (Phase II). These GCs expand, diversify, and select high-affinity variants of antigen-specific B cells for entry into the long-lived memory B cell compartment (Phase III). Upon antigen rechallenge, memory B cells rapidly expand and differentiate into PCs under the cognate control of memory Th cells (Phase IV). We review the cellular and molecular regulators of this dynamic process with emphasis on the multiple memory B cell fates that develop in vivo.

Antigen-specific memory b cell development

B cells obtain help from T cells in the antibody response by acting as antigen-specific antigen presenting cells. A direct signal through binding of antigen to membrane Ig can enhance B cell antigen presentation and T-dependent B cell activation, but is not required for a productive interaction between a small resting B cell and a differentiated helper T cell. As a result of helper T cell recognition of antigen on the B cell surface, the T cell becomes activated and in turn activates the B cell. T cell help has two components: lymphokines which act as growth and differentiation factors for B cells, and additional signals which require cell contact and enable B cells to respond to lymphokines. Contact help activity is regulated like lymphokine synthesis and secretion. Because contact help activity is retained by fixed, activated helper T cells and plasma membranes prepared from activated T cells, contact help is likely to be owing to new proteins expressed as membrane-bound lymphokines or activation antigens on helper T cells. Once induced, contact help can be delivered to B cells independently of recognition of antigen/class II MHC. A newly identified activation antigen of helper T cells, a ligand for the B cell differentiation antigen, CD40, is a key component of contact help. The roles of other T and B cell membrane molecules in contact help are reviewed.

T Cell-Dependent B Cell Activation

Rabbits primarily stimulated with a BSA (bovine serum albumin)-sulfanilic acid complex will produce a good secondary response to the sulfanilic acid hapten if the carrier used in the secondary stimulus is again BSA, and not if the secondary carrier is HGG (human gamma globulin). In the latter situation, a good secondary response is obtained, however, if the rabbits are pretreated a few weeks earlier with free HGG. We conclude that the immune stimulus involves the recognition of carrier determinants unrelated to the hapten. As the receptors for recognition of unrelated determinants are probably situated on different cells, we suggest that the immune stimulus leading to antibody formation requires the interaction of two antigen-bridged cells.

https://rupress.org/jem/article-pdf/129/6/1131/1392365/1131.pdf

N. K. Jerne

Papers

The requirement of more than one antigenic determinant for immunogenicity