The Chosen Few? Positive Selection and the Generation of Naive B Lymphocytes
1999; Cell Press; Volume: 10; Issue: 5 Linguagem: Inglês
10.1016/s1074-7613(00)80049-7
ISSN1097-4180
Autores Tópico(s)Immune Cell Function and Interaction
ResumoDeveloping lymphocytes must be tested at critical checkpoints to ascertain if they have made in-frame rearrangements of immune receptor genes and to determine if individual cells express potentially useful antigen receptors. Pre-B cells carrying in-frame rearrangements at the immunoglobulin heavy chain locus (78Rajewsky K Clonal selection and learning in the antibody system.Nature. 1996; 381: 751-758Crossref PubMed Scopus (1026) Google Scholar) are positively selected. Not every pre-B cell expressing a productively rearranged immunoglobulin heavy chain gene may undergo selection and expansion; selection mediated by the pre-B receptor may be based on reading frame choice as well as on considerations of the apparent usefulness of certain Ig heavy chains in the humoral repertoire. Some of the known selection and migration events during the development of naive B cells are depicted in Figure 1. Space limitations, coupled with an attempt to provide a fairly comprehensive list of mutations that affect cell selection events (Table 1, Table 2, and Table 3), have made it impossible for me to cite many of the contributions I originally wished to. I apologize in particular to the many whose work is mentioned but not cited.Table 1Mutations that Compromise Development at the Pre-BCR CheckpointaMutations that affect V(D)J recombination have not been listed.MurineMutationPhenotypeReferencesμTm segment−/−Block in B cell development at the pro-B to pre-B transition; RF2bRF2 refers to reading frame 2. Pro-B cells that use RF2 can make a Dμ protein and fail to differentiate further. 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Immunol. 1998; 159: 5273-5284Google ScholarAiolos−/−Decreased107Wang J.H Avitahl N Cariappa A Friedrich C Ikeda T Renold A Andrikopoulos K Liang L Pillai S Morgan B.A Georgopoulos K Aiolos regulates B cell activation and maturation to effector state.Immunity. 1998; 9: 543-554Abstract Full Text Full Text PDF PubMed Scopus (175) Google ScholarIL-5−/−Transient decrease52Kopf M Brombacher F Hodgkin P.D Ramsay A.J Milbourne E.A Dai W.J Ovington K.S Behm C.A Köhler G Young I.G Matthaei K.I IL-5 deficient mice have a developmental defect in CD5+ B-1 cells and lack esoinophilia but have normal antibody and cytotoxic T cell responses.Immunity. 1996; 4: 15-24Abstract Full Text Full Text PDF PubMed Scopus (387) Google ScholarIL-5Rα−/−Transient decrease112Yoshida T Ikuta K Sugaya H Maki K Takagi M Kanazawa H Sunaga S Kinashi T Yoshimura K Miyazaki J.-I et al.Defective B-1 cell development and impaired immunity against Angiostrongylus cantonensis in IL-5Rα deficient mice.Immunity. 1996; 4: 483-494Abstract Full Text Full Text PDF Scopus (149) Google Scholar Open table in a new tab Newly formed B lymphocytes that bear self-reactive antigen receptors may be silenced or eliminated in the bone marrow. 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An attractive explanation for why we require positive selection in the T lineage is the demonstrated requirement for MHC–self-peptide induced tickling of TCRs in the maintenance of peripheral and memory T cells (93Tanchot C Lemonnier F.A Perarnau B Freitas A.A Rocha B Differential requirements for survival and proliferation of CD8 naive or memory T cells.Science. 1997; 276: 2057-2062Crossref PubMed Scopus (650) Google Scholar). "Tickling" is now accepted terminology for a subliminal or low-intensity antigen receptor signal, usually linked to survival, as opposed to an overt heavy-duty "triggering" of the same receptor that might contribute to proliferation or death. It could be argued that developing B cells may also require to be positively selected by self-antigens. In such a scheme of things, memory B cells may potentially be tickled and kept alive by the same self-antigens that might be responsible for their emigration from the bone marrow and for their maintenance in the periphery as newly formed naive B cells. Immature B cells in the bone marrow are the first cells in this lineage to express a complete B cell receptor (BCR). These IgMhiIgD−/loCD23− cells express low levels of B220, high levels of the heat stable antigen HSA/CD24, and low levels of Bcl-2. Slightly more differentiated IgMhiIgDlo/−HSAhi cells expressing higher levels of B220 and Bcl-2 are also found in the bone marrow and are sometimes called transitional B cells (9Carsetti R Kohler G Lamers M.C Transitional B cells are the target of negative selection in the B cell compartment.J. Exp. Med. 1995; 181: 2129-2140Crossref Scopus (264) Google Scholar). Newly formed B cells in the spleen are phenotypically similar to these immature and transitional B cells in the bone marrow but express higher levels of B220 and Bcl-2. They rapidly differentiate into recirculating IgM+IgDhiCD23+ follicular B cells, which continue to express high levels of HSA for a few days, but subsequently mature into naive HSAint/lo cells. These latter cells constitute the major pool of long-lived naive B lymphocytes. The BCR, as will be discussed below, is required for the development of naive B cells. Does this requirement imply that this receptor is involved in a positive selection event or merely in a selection-neutral maturation process? There are two broad pieces of evidence that are frequently considered in support of the notion that immature B cells might be positively selected. It has been suggested that the repertoire of newly formed peripheral B cells is more limited than the repertoire of bone marrow B cells. Some studies have also suggested that only a small proportion of newly formed B cells may emerge in the periphery, indirectly implying that only properly selected cells find their way out of the bone marrow or receive signals that permit survival in the periphery. A comparison of VH gene usage in B220+IgM− pre-B cells in the bone marrow with IgD+ mature B cells in the spleen (32Gu H Tarlinton D Muller W Rajewsky K Forster I Most peripheral B cells are ligand selected.J. Exp. Med. 1991; 173: 1357-1371Crossref Google Scholar) suggested that there is a broader BCR repertoire in the bone marrow as compared to the periphery. This study raised the possibility that positive or negative selection events, or both, occurring either in the bone marrow or the periphery, may skew the naive B cell repertoire during development. A small proportion of the skewing observed in this particular study might have been generated at the pre-B stage itself by pre-B receptor–mediated selection (46Keyna U Beck-Engeser G.B Jongstra J Applequist S.E Jack H.-M Surrogate light chain mediated selection of Ig heavy chain V regions.J. Immunol. 1995; 155: 5536-5542Google Scholar, 109Ye J McCray S.K Clarke S.H The transition of pre-BI to pre-BII cells is dependent on the VH structure of the μ/surrogate L chain receptor.EMBO J. 1996; 15: 1524-1533Google Scholar, 96ten Boekel E Melchers F Rolink A.G Precursor B cells showing H chain allelic inclusion display allelic exclusion at the level of pre-B cell receptor surface expression.Immunity. 1998; 8: 199-207Abstract Full Text Full Text PDF Scopus (87) Google Scholar). In theory, if only a subset of newly generated B cells that had already emerged in the spleen were able to enter lymphoid follicles, some of the skewing of the repertoire could also occur at such a putative checkpoint (30Goodnow C.C Balancing immunity and tolerance deleting and tuning lymphocyte repertoires.Proc. Natl. Acad. Sci. USA. 1996; 93: 2264-2271Crossref Scopus (319) Google Scholar). There is no direct evidence, however, to suggest that follicular exclusion serves as a checkpoint during the differentiation of naive B cells (56MacLennan I.C.M B cell receptor regulation of peripheral B cells.Curr. Opin. 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In these analyses, phenotypically defined, newly generated immature B cells were shown to incorporate BrdU relatively rapidly and were estimated to have half-lives of about 3–4 days. It was recognized, however, that the short half-life did not necessarily imply a short cellular life span but could reflect the rapid transit of cells through a phenotypically distinct peripheral B cell subcompartment. It is estimated that a day after immature B cells reach the spleen, they begin to enter the recirculating follicular pool and may be distributed to all secondary lymphoid tissues (72Osmond D.G Population dynamics of bone marrow B lymphocytes.Immunol. Rev. 1986; 93: 103-124Crossref Google Scholar). It has also been suggested that only about 10%–20% of the immature B cells generated every day actually seed the peripheral long-lived pool (2Allman D.M Ferguson S.E Lentz V.M Cancro M.P Peripheral B cell maturation II. Heat stable antigenhi splenic B cells are an immature developmental intermediate in the production of long lived marrow derived B cells.J. Immunol. 1993; 151: 4431-4444Google Scholar). These and other similar estimations have relied on the examination in the periphery of only splenic B cells. Newly generated B cells may begin to recirculate quite rapidly, and B cells in peripheral lymphoid organs other than the spleen continue to express high levels of HSA as well as the pB130–140 marker, which also defines recent emigrants from the bone marrow (81Rolink A.G Andersson J Melchers F Characterization of immature B cells by a novel monoclonal antibody, by turnover and by mitogen reactivity.Eur. J. Immunol. 1998; 28: 3738-3748Crossref Scopus (197) Google Scholar). It is therefore possible that a larger proportion of B cells might actually emerge from the bone marrow than is sometimes assumed, but detailed studies examining all peripheral lymphoid organs at specific "chase" times have not yet been described. If, indeed, a large number of newly formed B cells do give rise to a considerably smaller number of mature cells, it nevertheless remains to be established where most of these immature B cells are lost. Cell loss could potentially occur in the bone marrow or at the time of follicular entry in the periphery. There is little evidence for the loss of immature B cells in the periphery, especially when one takes into account the distribution of newly formed B cells into secondary lymphoid organs other than the spleen (81Rolink A.G Andersson J Melchers F Characterization of immature B cells by a novel monoclonal antibody, by turnover and by mitogen reactivity.Eur. J. Immunol. 1998; 28: 3738-3748Crossref Scopus (197) Google Scholar). It has been assumed, therefore, that many immature B cells are lost in the bone marrow, and this may well prove to be correct. This loss might reflect negative selection or possibly the positive selection of a portion of the B cell repertoire. The possibility that large numbers of immature B cells go somewhere else to die, other than the spleen or the bone marrow, has not been investigated. An alternative view that requires consideration is that very few immature B cells might actually be lost during ontogeny. This would imply that only a small proportion of immature B cells might be deleted by negative selection and that BCR-driven B cell maturation does not necessarily involve a positive selection event. It has been suggested that the cells targeted for deletion by multivalent self-antigens may be transitional B cells in the bone marrow and the spleen (9Carsetti R Kohler G Lamers M.C Transitional B cells are the target of negative selection in the B cell compartment.J. Exp. Med. 1995; 181: 2129-2140Crossref Scopus (264) Google Scholar) rather than the immature B cell population in the bone marrow. The possibility has been raised, although direct in vivo evidence is lacking, that receptor editing might occur primarily in bone marrow B lineage cells, while B cell clonal deletion may occur most readily in the newly formed/transitional B cell population in the spleen (82Sandel P.C Monroe J.G Negative selection of immatu
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