In this article we speak about the network of idiotypes in the immune system. We start by defining the vocabulary we are going to use. We then discuss the structural basis of idiotypic determinants (i.e. antigenic determi­ nants on the antibody variable region; also called idiotopes) and of their complementary anti-idiotypic antibody binding sites (anti-idiotopes). Idi­ otopes and anti-idiotopes are encoded by antibody V, D, and J genes. The idiotypic repertoire thus reflects the repertoire of these genes as they are expressed, selected, and somatically modified in the immune system. The idiotypic repertoire, its genetic basis and its selection in ontogeny, is a main theme of the present view. This relates directly to the functional idiotypic network: Which rules do idiotypic interactions in the immune system follow and what is their physiological role? We will see that idiotypic interactions seem to be involved in the growth control of lymphocyte clones with defined receptor specificity and may thus be essential for the generation of a diverse system of interacting cells. They also stabilize the expression of a given receptor repertoire in active immune responses. Idiotypic interactions occur within the compartment ofB lymphocytes, but they also involve T cells. We discuss the crucial issue of whether or not recognition of B-cell idiotypes is one of the principles by which T cells are selected in the immune system. This article cannot deal with all facets of idiotypic research. We restrict ourselves largely to the discussion of experimental work in the mouse and, in particular, we do not discuss in any detail the role of idiotypic interac­ tions in regulatory T-cell circuits controlling immune responses. Detailed models of immunologic control through cell interactions have emerged from recent work in this field. We refer the disappointed reader to a few

Genetics, Expression, and Function of Idiotypes

We have examined the ability of two purified peptide fragments derived from hen (chicken) egg-white lysozyme (HEL); N-terminal, Co-terminal peptide (a.a. 1--17:cys 6--cys 127:120--129) and mixed disulfide LII peptide (LII) (a.a. 13--105) to induce antigen-specific suppression or help in B10 (H-2b) nonresponder and B10.A (H-2a) responder mice. An anti-HEL primary in vitro antibody response can be obtained in either strain by stimulation with HEL coupled to erythrocytes (RBC). Preimmunization with HEL-complete Freund's adjuvant-(CFA) or N-C-CFA-induced suppression of the anti-HEL PFC response to HEL-RBC in spleen cell cultures from B10 mice, whereas helper activity was demonstrated in cultures from B10.A mice similarly immunized. LII-CFA priming elicited helper cells in both C57BL/10 Sn (B10) and B10.A/SgSn (B10.A) mice. The genetic nonresponsiveness of B10 mice to HEL can therefore be attributed to the activation of suppressor T cells by a limited portion of the molecule (e.g., N-C) which prevent the potential response directed against other epitopes on the same molecule (e.g., LII). One manifestation of major histocompatibility complex gene activity appears to be the intramolecular selection of different antigenic determinants leading to activation of functionally different T-cell subpopulations.

https://rupress.org/jem/article-pdf/150/2/293/1090313/293.pdf

Fine specificity of regulatory T cells. II. Suppressor and helper T cells are induced by different regions of hen egg-white lysozyme in a genetically nonresponder mouse strain.

The following evidence, mainly presented here, suggests that IgD receptors play a crucial role in determining the potential for affinity maturation in memory B cell populations IgD receptors are present on the first memory B cells to appear after priming These memory cells give rise to more-mature memory cells that have lost their IgD receptors The proportions of early (IgD(+)) and mature (IgD(-)) memory cells found in individual donors vary with time, priming conditions, and the availability of T cell help, and both populations frequently coexist for long periods of time IgD(+) and IgD(-) memory cells carry IgG receptors and give rise to IgG responses with identical isotype representation in adoptive recipients IgD(+) memory cells, however, always give rise to predominantly low-affinity antibody responses, whereas IgD(-) memory cells consistently generate responses of substantially higher average affinity This affinity differential is maintained between early and mature memory populations in the same donor and does not appear to be a result of selective differentiation of higher-affinity IgD(+) memory cells into the IgD(-) memory pool Thus, the selective forces responsible for affinity maturation appear to operate mainly in mature memory cell populations that have already lost IgD receptors; or, stated conversely, little or no selection towards high-affinity memory appears to occur among memory cells that retain IgD receptors In discussing these findings, we suggest that the IgD receptors themselves are responsible for maintaining early memory populations at a lower average affinity than IgD(-) populations in the same animal The IgD receptors, we argue, serve to increase the antigen-binding capacity of lower-affinity memory cells so that these cells can survive, expand, and differentiate (to IgD(-)) at antigen concentrations that select against expansion of low- affinity memory cells no longer carrying IgD receptors Thus, when antigen is limiting, IgD(-) memory populations will be selectively expanded to higher average affinities, whereas coexisting IgD(+) populations will retain their initial affinity profile This hypothesis suggests that mechanisms that regulate expression and loss of IgD receptors are central to the adaptability of the immune system in its response to invading pathogens Two related roles can be envisioned for the IgD receptors in this regard First, they extend the lower boundary of the affinity range of early memory cell populations induced by a given antigenic stimulus and therefore broaden the diversity of responses obtainable from these populations Secondly, they support the persistence of low-affinity memory populations under conditions where antigen becomes limiting and eventually disappears These persisting populations then serve as a diversely reactive reservoir from which mature memory populations can be drawn with higher affinities either for the original antigen or, more importantly, for related antigens that the animal may subsequently encounter Thus the existence of IgD receptors on early memory cells maintains the full range of response diversity despite ongoing selective expansion of (mature) memory populations to produce antibodies with high combining affinities for individual antigens The flexibility inherent in such an organizational system, we believe, could be expected to account for the evolutionary development of IgD receptors and the regulatory capabilities that support operation of the system

https://rupress.org/jem/article-pdf/151/5/1071/1090714/1071.pdf

Memory B cells at successive stages of differentiation. Affinity maturation and the role of IgD receptors

O que vemos, não e’o que vemos, senão o que somos1

From an Antigen‐Centered, Clonal Perspective of Immune Responses to an Organism‐Centered, Network Perspective of Autonomous Activity in a Self‐Referential Immune System

C3H/HeJ T cells which specifically recognize B cell-surface antigens of the related, major histocompatibility complex-compatible C3H/Tif strain, can be substantially enriched in vitro by long-term exposure (2--6 wk) of primed lymph node cells to the relevant cellular antigens These enriched T cells contain functional helper cells as demonstrated by their capacity to induce large numbers of Ig-secreting plaque-forming cells (PFC) in cultures of antigenic B cells The cooperative interaction results in activation of a large fraction of all splenic B cells, with consequent exponential growth and maturation to high rate secretion of IgM, IgG1, and IgG2, but not IgG3 The IgM PFC response includes antibody specificities to a number of different antigens and can be considered, therefore, as polyclonal The T helper cell-dependent B-cell response is insensitive to inhibition by anti-delta antibodies, and in contrast with lipopolysaccharide-induced PFC responses, is only partially sensitive to the inhibitory effects of anti-mu antibodies Finally, B-cell activation to growth and maturation by helper T cells strictly required direct T-cell recognition of antigens on the surface of responding B cells, leading us to the conclusions that if any soluble factors are generated in the collaborative process, they are either antigen specific or incompetent to initiate B-cell growth

https://rupress.org/jem/article-pdf/151/3/587/1090732/587.pdf

Specific T helper cells that activate B cells polyclonally. In vitro enrichment and cooperative function.

Antigen-independent cooperation between T and B lymphocytes is demonstrated in vitro in two different experimental protocols: (a) B cells from A/J mice immunized in vivo either with Group A streptococcal vaccine (Strep.A) or with the IgG1 fraction of guinea pig anti-idiotypic antibody to the A5A idiotype, mature into plaque-forming cells (PFC) with specificity for Group A streptococcal carbohydrate (A-CHO) during a 4-day culture together with T cells from A/J mice immunized in vivo with A5A idiotypic antibody. (b) B cells from A/J mice immunized in vivo with Strep.A generate PFC specific for A-CHO when cultured in the presence of small concentrations of anti-A5A idiotypic antibody and of T cells primed with Strep.A. In both cases, antigenindependent cooperation is idiotypically selective, such that only those B cells respond that secrete antibody with the A5A idiotype.



The data are interpreted to suggest that, in addition to antigen-specific helper cells, idiotype-specific may participate in antibody responses, and that the latter type of help may be responsible for the idiotypic selectivity in T-B cooperation observed previously. Furthermore, idiotype-specific cooperation may be a means to generate and maintain B cell diversity during the evolution and ontogeny of the immune system.

Recognition of idiotypes in lymphocyte interactions. II. Antigen-independent cooperation between T and B lymphocytes that possess similar and complementary idiotypes.

K. Eichmann

Papers

Recognition of idiotypes in lymphocyte interactions. II. Antigen-independent cooperation between T and B lymphocytes that possess similar and complementary idiotypes.