How memory is retained is an immunological mystery. One possibility, argued here by Fons UytdeHaag and colleagues, is that memory is imprinted in the somatically-mutated Ig expressed by certain CD5+ B cells. The theory proposes that the Ig expressed by this self-renewing population acts as surrogate antigen, selecting and stimulating emerging antigen-specific lymphocytes

Heijden, R.W.J. (Roger) van der

Osterhaus, A.D.M.E. (Albert)

UytdeHaag, F.

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Maintenance of immunological memory: a role for CD5 + B cells? Fons UytdeHaag, Roger van der Heijden and Albert Osterhaus How memory is retained is an immunological mystery. One possibility, argued here by Fons UytdeHaag and colleagues, is that memory is imprinted in the somatically-mutated Ig expressed by certain CD 5 ÷ B cells. The theory proposes that the Ig expressed by this self-renewing population acts as surrogate antigen, selecting and stimulating emerging antigen-specific lymphocytes. Basic elements in life-long immunity against a pathogen include the generation and maintenance of immunologi- cal memory, that is the state of the immune system that results in a secondary immune response upon re- encounter with the antigen. The pathways of memory cell generation are well defined 1-4 but the mechanism(s) re- sponsible for the maintenance of immunological memory is poorly understood. In rodents, memory has been vari- ously ascribed to long-lived cells, to the continuous pro- liferation of mature antigen-specific cells and to the continuous input of newly formed short-lived cells from the bone marrow s-9. Persistence of antigen may be fun- damental to B-cell longevity, although there is no defini- tive proof 1°-14. Here, an alternative hypothesis is proposed for the maintenance of memory, based on the integration of B cells bearing somatically-mutated Ig, into the B-cell network. Development of 'memory' B cells After encountering T-cell-dependent or T-cell- independent antigen, a virgin, resting B cell either de- velops into an antibody-secreting plasma cell or a 'mem- ory' B cell that can respond upon re-encounter with antigen 1,3. Primary B cells and 'memory' B cells differ in many respects 3,1s. Most importantly, in a primary re- sponse, plasma cells usually produce unmutated, multi- reactive antibodies with low affinity for the antigen, whereas activation of 'memory' B cells results in the production of specific antibody with high affinity for the antigen. Somatic hypermutation, acting selectively on rearranged antibody variable region genes, and antigen- driven selection of mutations are the basis of affinity maturation of the specific antibody molecules expressed by 'memory' B cells 1-3,16 18. CD5 + B cells The investigation of B-cell development in mice has revealed two B-cell 'lineages' that appear to develop along separate differentiation pathways (see Refs 19 and 20 for review). B cells emerging continuously from the bone marrow enter the periphery and may be selected by antigen into conventional immune responses (vide su- pra). A functionally distinct 'lineage' of B cells, express- ing the CD5 (Ly-1) molecule and apparently not participating in conventional immune responses, arises early in ontogeny, possibly from a source of stem cells independent of the bone marrow 19-22. These B cells, which predominate in early life but represent only a minor fraction of the B cells in the adult 23, appear to have the capacity for self renewal 24. They make up a pro- portion of the B cells that express immunoglobulin with inherent low affinities for self antigens 2s. They produce the so-called natural IgM antibodies that display multi- reactivity and harbor specificities for certain bacterial antigens 19,2°,24,26-29. In humans, CD5 + B cells (Leu-1 +) with similar functional characteristics exist 3°-32 (see Refs 19 and 20 for review). CD5 + B cells in both humans and mice frequently express VH and VL germ-line genes in the absence of somatic mutation 33-36. However, recently we 37 and others 38 have identified somatic mutations in expressed V H genes that lead to amino acid replacements, which accumulate in the complementarity-determining regions, CDR-I and CDR-II, in human CD5 + Epstein-Barr virus (EBV)-transformed peripheral blood B cells of healthy adults or patients with rheumatoid arthritis 3s. These observations indicate that somatic mutants of CD5 + B cells may be selected by antigen. In the mouse the possi- bility that V genes of CD5 + B cells can be subject to antigen-driven somatic hypermutation has not been directly addressed. Immune networks In the mouse there is a high frequency of mutual V H region interactions, known as connectivity, within the set of antibodies that arises during early B-cell ontogeny22, 39,4°. A large part of this early repertoire is constituted by B cells belonging to the CD5 + B-cell 'lineage' (see Refs 19 and 20 for review). Because of the autonomous activities of CD5 + B cells and the self reactivity and high connectivity of their IgM antibodies, it has been proposed that these cells and their secreted antibodies establish immune networks by interacting with self constituents, including elements of the immune system itself 41. These immune networks may be essential in the initial development ofB-cell and T-cell repertoires, in self-nonself discrimination and in the maintenance oftolerance and memory 41,42. Immune networks may have little to do with conventional immune responses, which ~) 199 I, Elsevier Science Publishers [ td, UK. I) 16=--4919191/S02,00 Immunology Today 439 Vol 12 No. 12 1991 ii iii!ili ii  i iiii iii     iiii!iiiiiiiiii!iii!ii !ii!iiii ii!ill Bone marrow stem cell "2 Stem cell Antigen Antigen Virgi~l ~ \ Second / ",,~esponse Plasma cells 'Memory' B cell / r \  Plasma cells Multireactive unmutated CD5 + B cell Anti-idiotype memory-retaining CD5 + B cell Fig. 1. A possible scheme for the generation and maintenance ofB-cell memory is shown. Solid arrows indicate selection~stimulation by antigen/ idiotype; open arrows indicate affinity maturation of antibody V regions; circles with arrows indicate capacity for self renewal. are proposed to be discrete, nonnetworked responses that are selected by external antigen 41,42. How can memory be a property of an immune network if memory B cells originate in the 'unconnected set' ? It has been proposed that, although disconnected from immune networks when functioning as effector cells, 'memory' B cells do make connections with immune networks and these interactions determine their survival as 'memory' cells in the resting state. From this viewpoint, survival of lymphocytes in the resting state and the activation of effector functions or proliferation, as well as their decline, are determined bythe affinities and concentrations of the receptors involved in the clonal interactions 41,42. It is our contention that he influence of immune networks on the lifespan of'memory' B cells is due to regulation or control of clonal responses to antigen by networks, rather than 'imprinting the experience of the immune system with antigen in immune networks '41, which would make memory areal systemic property. How does the immune system 'learn about antigens'? Perhaps this occurs via idiotype-driven somatic mutation and selection of antibody V regions of CD5 + B cells. Memory: a systemic property Repeated stimulation with the same external antigen results in clonal proliferation and selection of somatic B-cell mutants that express high-affinity receptors for the antigen (see Fig. 1, arrows 1 and 2). Somatic mutation may alter the V regions of antigen- specific 'memory' B-cell clones such that their V regions interact with V regions of one or more members of the interconnected B-cell network. This does not necessarily imply an integration of these antigen-specific B ells into a network. Because of the temporarily increased clone sizes of anugen-specific 'memory' B cells during the response to antigen, and the greatly increased concen- trations of their somatically-mutated V regions, the anti- idiotypic CD5 + B-cell clones to which they fit will be stimulated to clonal expansion (see Fig. 1, arrow 3). We propose that V region genes encoding anti-idiotype anti- bodies of CD5 + B cells of immune networks are subject to a process of somatic hypermutation a d are then selected by somatically-mutated idiotypes of 'memory' B-cell clones (see Fig. 1, arrow 4). In this way anti-idiotypic CD5 + B cells, which really carry memory in the form of the imprint of the experience ofthe immune system with antigen, are expanded. Consequently, after antigen clear- ance, the somatically mutated antibody V regions of these anti-idiotypic memory B cells may stimulate the clonal expansion of mature antigen-specific 'memory' B cells or simply keep these cells alive as 'long-lived' resting cells (see Fig. 1, arrow 5). In either case, immunological memory is maintained in the absence of antigen by a population of self-renewing B cells, the somatically- mutated V regions of which mimic antigen. In addition, the memory-retaining CD5 + B cells could Immunology Today 440 vol 12 No. 12 1991 select virgin resting B cells or pre-B cells, which daily emerge in adult bone marrow (see Fig. 1, arrow 6). In contrast o anti-idiotypic CD5 + B cells, which are oper- ative in the development of repertoires during on- togeny 41,42, anti-idiotypic memory-retaining CD5 + B cells will select for specificity rather than connectivity. In other words, anti-idiotypic memory-retaining CD5 ÷ B cells expressing somatically-mutated antibody V regions that mimic antigen will select B cells with those combi- nations of germ-line V genes that are most likely to give rise to high-affinity antibody upon re-encounter with antigen (see Fig. 1, arrows 6 and 7). This proposition raises questions related to the basis of connectivity in immune networks: if antibody V regions of CD5 ÷ B cells are subject to somatic hypermutation a d now select antigen-specific V regions, how, if at all, is their connectivity in immune networks maintained? Per- haps the nucleotide sequences in framework I (amino acid residues 6-24) and in framework III (amino acid residues 67-85) that are conserved between human and murine VH genes of related families 43 will help to provide an answer. The conservation of these VH-family-specific coding sequences i especially striking among VH genes that are preferentially expressed in the early B-cell reper- toire. Kearney and co-workers 22 postulated a role for these conserved sites on natural IgM antibodies in estab- lishing connectivity in the developing immune networks. We recently described a human EBV-transformed, CD5 +, anti-idiotypic B-celt clone from peripheral blood lymphocytes of a healthy adult deliberately immunized with rabies virus vaccine 37. This clone showed mono- reactivity and high affinity (K d = 8.67 x 10 -9 mol 1 -l) for its idiotype, which is located in or near the combining site of a monoclonal antibody mapping alinear epitope of the rabies virus glycoprotein 44. Remarkably, the VH gene encoding this antibody showed, apart from amino acid replacements in CDR-I and CDR-II, five amino acid replacements in framework III, three of which were located in the conserved site spanning residues 67-85 (Ref. 37). It is, therefore, conceivable that an anti- + idiotypic memory-retaining CD5 B-cell clone selects for specificity when its V region mimics antigen and it can no longer establish connectivity, that is when the anti- body framework III region is modified by somatic mutations. A corollary of this theory is that, although memory is retained exclusively within anti-idiotypic CD5 + B-cell clones and is thus a property of B cells that have orig- inated from immune networks, memory is not necessarily distributed in immune networks, because anti-idiotypic memory-retaining CD5 + B cells have become dis- connected. We have refrained from discussing a possible role for T cells in the generation and maintenance of immunologi- cal memory. Melchers 4s recently proposed a model in which two B cells expressing complementary somatically- mutated antibody V regions act in concert with T cells to maintain immunological memory. In his model, pro- cessed idiotypic fragments presented via major histocom- patibility complex (MHC) class I or class II molecules may activate helper or cytotoxic (suppressor) T cells, respectively, thereby regulating the response of the re- spective B-cell clones. In conclusion, we propose that somatically-mutated antibody V regions of CD5 + anti-idiotypic memory B cells, which have the capacity for self renewal, may maintain B-cell memory in the absence of antigen. In addition, it is conceivable that these structures also act as 'crossreactive peptides '14 in the maintenance of T-cell memory 46. The authors thank N. Bos, J.D. Capra, A. Coutinho, F. Kroese, M. Marcos, F. Melchers, J. Urbain and many colleagues from our laboratory for the stimulating discussions that have initiated the writing of this paper, and C. Kruyssen, M. Eskens and R. Stokking for handling the manuscript. 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Maintenance of immunological memory: A role for CD5+ B cells?

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