cd5 expression in human b-cell populations
TRANSCRIPT
V I E W P O I N TI M M U N O L O G Y TO D AY
3 1 2 V o l . 2 0 N o . 7J U L Y 1 9 9 9
mmunoglobulin (Ig) is the definitivemarker of all B cells, which can se-crete antibodies at high rates as fullymature plasma cells. However, the
complexity being defined in the B-cell com-partment has required that models based onthe concept of a single B-cell populationmust be reappraised1. The finding that the T-cell marker CD5 was expressed by a smallproportion of normal B cells2 led to the con-cept that B cells comprise at least two mainsubpopulations (B-1 and B-2)3. B-1 cells en-compass the CD51 subpopulation, whereasB-2 cells represent the conventional B-cellsubpopulation. Nevertheless, there is stillmuch debate over their lineage origins, es-pecially in humans, and a great deal of effort has been put into trying to understand the significance of CD51 B cells in health anddisease states.
Subpopulations of B cellsAdvances in leukocyte phenotyping allowed the B-1 subpopulationto be divided into B-1a and B-1b cells (the Ôsister populationÕ). B-1bcells lack cell surface CD5, but share all the other attributes of B-1a
cells, such as the presence of the myelomono-cytic marker Mac-1 (CD11b/CD18) and thelow expression of the high molecular weightisoform of the common leukocyte antigen(CD45RA). However, these cells possessmRNA for CD5 despite the lack of surfaceCD5 (Ref. 4) and it can be shown that EpsteinÐBarr virus-stimulated CD5-/CD45RAlo Bcells can express CD5 mRNA at levels com-parable with those of their surface CD51
counterparts5. Unlike mice and humans,other species do not appear to have CD5-defined B-cell subpopulations and virtuallyall the B cells of the rabbit are CD51 (Ref. 6).
The most significant feature of classic B-1cells, as defined in mouse and humans, is
their production of low-affinity polyreactive Igs (Ref. 7). These anti-bodies recognize a variety of autoantigens and crossreact with manybacterial antigens, including polysaccharides and lipopolysacchar-ides. In addition, CD51 B cells show an increased propensity for malignant transformation8, and we showed that B cells from patientswith chronic lymphocytic leukaemia (CLL) are programmed to pro-duce multispecific autoantibodies9. Thus, classic B-1 cells appear to be mainly T-cell independent, although they are positively influenced by T-cell-derived cytokines.
41 Bancroft, G.J., Schreiber, R.D. and Unanue, E.R. (1991) Immunol. Rev. 124,
5Ð24
42 Dunn, P.L. and North, R.J. (1991) Infect. Immun. 59, 2892Ð2900
43 Ladel, C.H., Blum, C. and Kaufmann, S.H.E. (1996) Infect. Immun. 64,
1744Ð1749
44 Emoto, Y., Emoto, M. and Kaufmann, S.H.E. (1997) Infect. Immun. 65,
5003Ð5009
45 Flesch, I.E., Wandersee, A. and Kaufmann, S.H.E. (1997) J. Immunol. 159,
7Ð10
46 Collins, H.L., Schaible, U.E. and Kaufmann, S.H.E. (1998) J. Immunol.
161, 5546Ð5554
47 Rhoades, E.R., Cooper, A.M. and Orme, I.M. (1995) Infect. Immun. 63,
3871Ð3877
48 Cooper, A.M., Dalton, D.K., Stewart, T.A. et al. (1993) J. Exp. Med. 178,
2243Ð2247
49 Holland, S.M. (1996) Semin. Respir. Infect. 11, 217Ð230
50 Lu, B., Rutledge, B.J., Gu, L. et al. (1998) J. Exp. Med. 187, 601Ð608
51 Chensue, S.W., Warmington, K.S., Ruth, J.H. et al. (1995) J. Immunol. 154,
5969Ð5976
52 Chensue, S.W., Warmington, K.S., Ruth, J.H. et al. (1998) J. Immunol. 157,
4602Ð4608
53 Chensue, S.W., Warmington, K.S., Ruth, J.H. et al. (1997) J. Immunol. 159,
3565Ð3573
54 Kindler, V., Sappino, A.P., Grau, G.E. et al. (1989) Cell 56, 731Ð740
55 Flynn, J.L., Goldstein, M.M., Chan, J. et al. (1995) Immunity 2, 561Ð572
56 Smith, D., Hansch, H., Bancroft, G. et al. (1997) Immunology 92,
413Ð421
57 Kaufmann, S.H.E. and Kaplan, G. (1996) Res. Immunol. 147, 487Ð489
CD5 expression in human B-cellpopulations
Pierre Youinou, Christophe Jamin and Peter M. Lydyard
The origin of CD51 B cells remains
controversial. The differential
response to ligation of CD5
resulting in apoptosis or
proliferation provides insight into
its roles in distinct human B cells.
Here, Pierre Youinou, Christophe
Jamin and Peter Lydyard review
current knowledge of B-1 and B-2
cells, and propose that CD5 has
different functions when expressed
by different B-cell subpopulations.
I
0167-5699/99/$ – see front matter © 1999 Elsevier Science. All rights reserved. PII: S0167-5699(99)01476-0
V I E W P O I N TI M M U N O L O G Y TO D AY
V o l . 2 0 N o . 7 3 1 3J U L Y 1 9 9 9
Separate lineage or activation marker?Some evidence has been obtained to support the argument that B-1and B-2 cells follow distinct developmental pathways. Consistentwith this view is the striking similarity in the relative proportion ofcirculating CD51 B cells in monozygotic twins10 and family membersof patients with rheumatoid arthritis11. Initial experiments claimedthat B-1 but not B-2 cells produced interleukin 10 (IL-10)12. Further-more, transfer experiments showed that the injection of B-1-enrichedperitoneal B cells into irradiated mice reconstituted the B-1 but notthe B-2 compartment, whereas cells from the bone marrow (BM) resulted in engraftment of B-2 but not B-1a cells13. There is also someevidence that, in the presence of fibroblast-conditioned medium, B-1a cells can develop in vitro macrophage markers and functions14.
The alternative view is that B-1 and B-2 are representatives of dif-ferent developmental/activation stages of a single B-cell lineage15.CD5 can indeed be induced on many B cells by a variety of stimuli.For example, the mitogen, phorbol 12-myristate 13-acetate (PMA),promotes expression of CD5 by human malignant16 and normalCD52 B cells. Similar data are now available in the mouse in whichCD52 B cells are induced to express CD5 after treatment with anti-IgM antibodies and IL-6 (Ref. 17) or after transformation of thepre-B cell lines with retroviruses expressing v-H-ras18. It has alsobeen demonstrated recently that CD52 B cells synthesize as much IL-10 as CD51 B cells during mitogen- or antigen-driven responses,indicating that B cells produce IL-10 independent of CD5 expression19.
Anatomical distribution of CD51 cellsB cells originate from precursors in the omentum20, yolk sac and fetal liver, in both humans and mouse, and this function is takenover by the BM. In humans, very high percentages of B-1a cells in thefetal circulation diminish to 60Ð80% in umbilical cord blood (CB)21.Thereafter, a decrease is seen in the peripheral blood (PB) with age22,so that as few as 5Ð30% of the circulating B cells are B-1a in adults23;4Ð6% are B-1b and 65Ð89% are B-2 cells4. The first B cells to appear inthe fetal liver and the developing lymph nodes are virtually 100%CD51 (Ref. 24). In one study, almost all the IgM1 B cells were shownto be CD51 in two fetal liver samples from approximately six-month-old fetuses7. In fetal spleen, 40Ð60% B-1 cells are detectable at19Ð22 weeks. Less than 10% are found in the adult human spleenand less than 30% in lymph nodes, where they are scattered at theedge of the germinal centres25. As is found in the tonsils, they aremainly located within the follicular mantle zone (FMZ)26. By con-trast, they are virtually absent in human adult BM. The major site ofCD51 B cells in the mouse is the peritoneal cavity (perC), where theyrepresent 30Ð60% of the total cells27. It has been reported that most Bcells in the human perC are also CD51, where 19Ð76% of the B cellsare CD51, compared with 11Ð49% in the circulation28.
Ligands for CD5A number of ligands have thus far been described for CD5 in differ-ent species (Table 1).
CD72The first ligand29 for CD5 was identified as the pan-B cell markerCD72. It was thought that, because most T cells express CD5, ligationof CD72 was a necessary costimulus of B cells after cognate inter-actions with T cells30. However, receptor crosslinking is not requiredfor signalling human B cells through CD72 (Ref. 31). Because humanCD51 B cells have a tendency to express low-affinity polyspecificantigen receptors, and occupancy of CD72 results in enhanced stimu-lation through the antigen receptor32, it is possible that B-1 cells serveas antigen-presenting cells for B-2 cells33. The importance of CD72 asa ligand is emphasized by our observation that the density of CD72is directly related to that of CD5 (Ref. 34). Furthermore, unlike CD5, CD72 is not capped with surface IgM (Ref. 35) and is,therefore, not part of the B-cell receptor complex (BCR), although itis modulated by treatment with anti-IgM or anti-CD5 antibodies(Ref. 36).
Ig framework sequencesIn the rabbit, all B cells express CD5 and the majority use a singleVH1 gene to encode their BCR (Ref. 37). F(ab9)2 fragments of anti-bodies that express VH a2 framework sequences, the product of thissingle VH1 gene, have been shown to bind to CD5 (Ref. 38). Such aninteraction, either on the same or adjacent cells, might result in a positive selection event.
Ligand on activated spleen cellsAn additional ligand for CD5 has recently been identified in themouse39. This inducible T-cell-dependent ligand expression is foundon antigen-activated splenic T and B cells and has convincingly beenshown to be different from CD72 by distribution and immuno-precipitation studies. Therefore, the binding of CD5 to this lectin onactivated lymphocytes could play a role in T-cell/B-cell costimu-lation during a T-cell-dependent immune response, perhaps throughcytokines.
There is more than one kind of CD51 B cellThus far, evidence has been presented that most or all B cells can potentially express CD5. Our hypothesis is that there are differencesbetween CD51 B cells that arise during ontogeny and those on whichCD5 has been induced by various stimuli (Ôinduced CD51 cellsÕ).These two kinds of CD51 B cells coexist in normal humans and mice
Table 1. Different ligands for CD5
CellLigand Species populations Refs
CD72 Human, mouse All B cells 29Ig VH framework Rabbit Some B cells 38Antigen-induced Activated Tglycoprotein Mouse, human and B cells 39
V I E W P O I N TI M M U N O L O G Y TO D AY
3 1 4 V o l . 2 0 N o . 7J U L Y 1 9 9 9
and originate from distinct B stem cells (Table 2). A correlate to thisinterpretation is that B-1 cells endogenously carrying CD5 mighthave a different function from other B cells induced to express CD5after activation. Consequently, it is reasonable to assume that signalling via CD5 on these two populations could occur throughdifferent ligands.
Evidence from differential effects of CD5 ligation Proliferative stimuli Using tonsillar CD51 B cells, it has been shown that anti-CD5 monoclonal antibody, used as a surrogate ligand, had no direct pro-liferative effect, but sustained the proliferative response in cultureswith IL-2 and anti-IgM (Ref. 35).
Induction of apoptosis Incubation of human tonsillar B cells with anti-CD5 alone, in the ab-sence of IL-2 or anti-IgM, resulted in apoptosis by 48 h. Ligation ofeither CD5 or of surface IgM triggered apoptosis. This is consistentwith a negative role for CD5 in proliferation, as mouse perC B-1 cellswere induced into apoptosis by anti-IgM but proliferated when theB-1 cells were taken from CD5-deficient mice40. Under the same con-ditions of treatment, engagement of CD5 or CD3 on blood T cellsfailed to induce apoptosis, indicating that there are important differ-ences in the function of CD5 molecules on tonsillar B cells, comparedwith circulating T cells. Furthermore, Cerutti et al.41 recently reportedthat crosslinking CD5 molecules enhances the expression of IL-2 andtumour necrosis factor a receptors on B-1a cells from umbilical CB,but not on B-1a cells from CLL patients, the normal counterparts ofwhich are localized within the FMZ of secondary lymphoid organs42.It is possible that signalling via CD5 might be similar in CLL cellscompared with Ônormal CD51 cellsÕ, suggesting that the two kinds of
CD51 B cells respond differently to ligation of CD5. Although wefavour the concept of two populations responding differently to CD5 ligation, such populations might represent the same B-cellpopulation at different stages of differentiation.
Characteristics of two putative CD51 B-cellpopulationsConstitutive expression of CD5 Murine B-1a cells are produced by B stem cells that home to theperC, where they maintain their numbers in adult life by virtue oftheir self-replenishing nature. Moreover, they exert a feedback regu-lation that limits de novo production of B-1 cells from progenitors43.The CD19 receptor plays a pivotal role in regulating production of Bcells and, perhaps through its ability to amplify membrane IgM sig-nalling, in the self-renewal of classic B-1a cells44. The first B cells tocolonize lymph nodes in humans derive from such stem cells, whichalso presumably seed the perC in humans. In addition, mouse (andpossibly human) perC B-1 cells contain a subset of IgA plasma cellprecursors that have the potential to traffic to the intestinal laminapropria, thus suggesting a role in mucosal immunity45.
After these early events, new B stem cells migrate to the BMwhere there is a developmental switch in B-cell lymphopoiesis froma fetal type to an adult type. Under the influence of the local envi-ronment, new B stem cells would differentiate into B-2 cells. How-ever, adult BM contains residual fetal lineage-derived B cells (presumably B-1b cells), precommitted to later expression of CD5(Ref. 46), and indeed the recovery of immune cells after BMtransplantation recapitulates fetal ontogeny, with CD51 B cells being regenerated regardless of the age of the donor47.
Induced expression of CD5 B-2 cells derive from the BM and migrate to secondary lymphoid organs where they respond to a plethora of foreign antigens, most ofwhich are T-cell dependent. Transfer experiments in the mouse48
suggest that such B-1b or B-2 cells, which differ from classic B-1acells and poorly reconstitute germinal centres, usually do not partici-pate in T-cell-dependent immune reactions. A proportion of FMZ B-cells in the tonsil are CD51 (Ref. 26) and it is hypothesized thatCD5 expression by these cells is induced there. Thus, 38Ð45% ofCD51 B cells are present in the small cell fraction of human tonsils(resting or in early activated state) and only ~7% are found in themedium-sized B-cell population (activated cells)49. It cannot be excluded that such cells acquire their CD5 before entry into the FMZ(for example, from the mucosa). Follicular mantle CD51 B cells arethe progenitors of CLL cells and can be induced to differentiate intoCD5- B cells with features of germinal centre cells50. This indicatesthat, after the transient expression of CD5 in the FMZ, most of thecells become CD52 again in the environment of the germinal centre. Nonetheless, very low numbers of CD51 B cells exist at thissite51, but these could either be classic or induced B-1a cells. Suchlosses of CD5 might account for the cell-free CD5 molecules detectablein autoimmune conditions52, where B-cell activation is prominent.
Table 2. Characteristics of two CD51 B-cellpopulations
Constitutive Inducedexpression expression
Characteristics of CD5 of CD5
Origin Early B stem cell Bone-marrow(self-replicating) stem cell
Anatomical Blood (cord and Follicular distribution adult), peritoneal mantle (? adult
cavity blood)Ligation of CD5 Induction of TNF-a Induction of
and IL-2 receptor apoptosisLigands CD72 (? framework CD72 (?
IgM) activation-inducedglycoprotein)
Abbreviations: IL-2, interleukin 2; TNF-a, tumour necrosis factor a.
V I E W P O I N TI M M U N O L O G Y TO D AY
V o l . 2 0 N o . 7 3 1 5J U L Y 1 9 9 9
Additional support for a distinction between classic B-1 cells andthose induced to express CD5 comes from gene usage studies of dis-ease Ð associated B1a cells. Whereas normal B-1a cells carry rela-tively unmutated variable region genes in the mouse53, as well as inhuman cord and adult blood54, somatically mutated V genes havebeen described in cases of FMZ-derived CLL and CD51 B cells pro-ducing high-affinity autoantibodies55. Therefore, disease-associatedCD51 B cells may derive from B-1b or B-2 cells.
Relationships between ligand and functionExtrapolating from the data in rabbits37,38, human fetal B-cell surfaceIg framework sequences might be the ligand for CD5 on B cells thatconstitutively express CD5. Such an interaction would affect main-tenance and selective expansion of particular B cells, and could beconsidered as a B-cell-derived superantigen. We have found that CBB cells frequently use VH4 genes for their Ig receptors56, and it hasbeen suggested that microbial superantigens (or even endogenoussuperantigens) select these particular B cells. Most adult PB B cellsuse VH3 genes and these may have been selected by internal super-antigens analogous to Staphylococcus aureus protein A. Thus, it is poss-ible that during early development ligation of CD5 results in selec-tion. In this situation, idiotypic/anti-idiotypic CD51 B cells would bepositively selected because crosslinking of only surface IgM on B-1acells leads, not to proliferation, but to apoptosis, whereas an interac-
tion between VH framework and CD5 resultsin survival.
The presence of CD5 seems to inhibit re-sponses of adult B cells through IgM, unlessthe CD5 is crosslinked or kept away fromthe antigen receptor. In the presence of CD5,murine perC B cells fail to proliferate in re-sponse to anti-IgM, but do so after crosslink-ing with anti-CD5 (Ref. 35). Such a negativerole for CD5 is also seen in the control of T-cell receptor-mediated signalling in devel-oping thymocytes57. Importantly, the STAT-3transcriptional activator is constitutively tyrosine-phosphorylated in perC B-1a cells58,strongly indicating that these cells are acti-vated by cytokines in the perC. This mightsubstitute for the BCR-mediated signal, andCD5 would keep the threshold of this signalat a level insufficient to induce proliferation,but sufficient to provide the signals that pro-mote the survival of classic B-1a cells59. Sucha ÔticklingÕ of cells through CD5 ligation hasrecently been suggested to occur60.
Concluding remarksThe constitutive or induced expression ofCD5 by human B cells suggests a pleiotropicrole for this molecule depending, not only
on the origin of the stem cell, but also on the microenvironment and,possibly, its ligand. The behaviour of the proposed different CD51 Bcells is summarized in Fig. 1. The biochemical mechanisms leadingto apoptosis rather than survival and proliferation after CD5 ligationare uncertain. However, it is possible that different CD5-associatedprotein tyrosine phosphatases might be involved.
The authors are indebted to I.M. Roitt and F. Caligaris-Cappio for advice and
helpful discussions. Thanks are also due to P. H�lary for secretarial assistance.
This research was supported by the Conseil R�gional de Bretagne and the
Communaute Urbaine de Brest, France, and the Medical Research Council,
UK.
Pierre Youinou ([email protected]) and Christophe Jamin are at theLaboratory of Immunology, Institut de Synergie des Sciences et de la Sant�,Brest University Medical School Hospital, BP 824, F-29609 Brest Cedex,France; Peter Lydyard is at the Dept of Immunology, Royal Free and University College London Medical School, Windeyer Building, 46 Cleve-land Street, London, UK W1P 6DB.
References1 Caligaris-Cappio, F. and Ferrarini, M. (1996) Immunol. Today 17, 206Ð208
2 Caligaris-Cappio, F., Gobbi, M., Bofill, M. and Janossy, G. (1982) J. Exp.
Med. 155, 623Ð628
IgM CD5 IgM CD5
B-1aSerous cavities
Mucosa
'Classical' CD5+ B cells 'Induced' CD5+ B cells
Proliferation
Germinal centre
Apoptosis
Mantle zone
IgM CD5 IgM CD5
IgM
B-1b/B-2
T cell(a) (b)
Fig. 1. (a) Cord blood B-1a cells, with increased levels of STAT-3 are maintained in the serous cavitiesand possibly mucosa through interactions between CD5 and a ligand together with local cytokines,such as interleukin 10 (IL-10). (b) By contrast, B-1b or B-2 cells are transiently induced to expressCD5 in the follicular mantle zones of secondary lymphoid tissues. Here, they undergo apoptosisthrough interaction with CD72 or another ligand, unless they receive a rescue signal by cognate interaction with T cells. This leads to migration into the germinal centre, loss of Ig and CD5 and subsequent proliferation and antigen selection.
V I E W P O I N TI M M U N O L O G Y TO D AY
3 1 6 V o l . 2 0 N o . 7J U L Y 1 9 9 9
3 Kantor, A.B. (1991) Immunol. Today 12, 389Ð391
4 Kasaian, M.T., Ikematsu, H. and Casali, P. (1992) J. Immunol. 148,
2690Ð2702
5 Paavonen, T., Quartey-Papafio, R., Delves, P.J. et al. (1990) Scand. J.
Immunol. 31, 269Ð274
6 Raman, C. and Knight, K.L. (1992) J. Immunol. 149, 3858Ð3864
7 MacKenzie, L., Youinou, P., Hicks, R. et al. (1991) Scand. J. Immunol. 33,
329Ð335
8 Caligaris-Cappio, F., Gottardi, D., Alfarano, A. et al. (1993) Blood Cells 19,
601Ð613
9 Br�ker, B.M., Klajman, A., Youinou, P. et al. (1988) J. Autoimmun.
1, 449Ð481
10 Kipps, T.J. and Vaughan, J.H. (1987) J. Immunol. 139, 1060Ð1064
11 Youinou, P., Le Goff, P., Merdrignac, G. et al. (1990) Arthritis Rheum. 33,
339Ð348
12 Ishida, H., Hastings, R., Kearney, J. and Howard, M. (1992) J. Exp. Med.
175, 1213Ð1220
13 Hayakawa, K., Hardy, R.R., Herzenberg, L.A. and Herzenberg, L.A.
(1985) J. Exp. Med. 161, 1554Ð1568
14 Borrello, M.A. and Phipps, R.P. (1996) Immunol. Today 17, 471Ð475
15 Haughton, G., Arnold, L.W., Whitmore, A.C. and Clarke, S.H. (1993)
Immunol. Today 14, 84Ð91
16 Miller, R.A. and Gralow, J. (1984) J. Immunol. 133, 3408Ð3414
17 Ying-zi, C., Rabin, E. and Wortis, H. (1991) Int. Immunol. 3, 467Ð476
18 Weichert, T.R. and Schwartz, R.C. (1997) Immunology 31, 79Ð84
19 Gieni, R.S., Umetsu, D.T. and de Kruyff, R.H. (1997) Cell. Immunol. 175,
164Ð170
20 Solvason, N., Lehuen, A. and Kearney, J.F. (1991) Int. Immunol. 3,
543Ð550
21 Lydyard, P.M., Quartey-Papafio, R., MacKenzie, L. et al. (1990) Scand. J.
Immunol. 31, 33Ð43
22 Hannet, I., Erkeller-Yuksel, F., Deneys, V., Lydyard, P.M. and
De Bruy�re, M. (1992) Immunol. Today 13, 215Ð218
23 Lydyard, P.M., Youinou, P. and Cooke, A. (1987) Immunol. Today 8, 37Ð39
24 Bofill, M., Janossy, G., Janossa, M. et al. (1985) J. Immunol. 134, 1531Ð1538
25 Gobbi, M., Caligaris-Cappio, F. and Janossy, G. (1983) Br. J. Haematol. 54,
393Ð403
26 Donno, M., Burgio, V.L., Tacchetti, C. et al. (1996) Eur. J. Immunol. 26,
2035Ð2042
27 Hayakawa, K., Hardy, R.R. and Herzenberg, L.A. (1985) J. Exp. Med. 161,
1554Ð1568
28 Nisitani, S., Murakami, M., Akamizu, T. et al. (1997) Scand. J. Immunol.
46, 541Ð545
29 van de Velde, H., von Hoegen, I., Wei, L., Parnes, J.R. and
Thielemans, K. (1991) Nature 351, 662Ð665
30 Kamal, M., Katira, A. and Gordon, J. (1991) Eur. J. Immunol. 21,
1419Ð1424
31 Kamal, M., Knox, K., Finney, M., Michell, R.H., Holder, M.J. and
Gordon, J. (1993) FEBS Lett. 319, 212Ð216
32 Katira, A., Kamal, M. and Gordon, J. (1992) Clin. Exp. Immunol. 76,
422Ð426
33 Gordon, J. (1994) Immunol. Today 15, 411Ð417
34 Jamin, C., Lamour, A., Pennec, Y.L., Hirn, M., Le Goff, P. and Youinou, P.
(1993) Clin. Exp. Immunol. 92, 245Ð250
35 Jamin, C., Lydyard, P.M., Le Corre, R. and Youinou, P. (1996) Scand. J.
Immunol. 43, 73Ð80
36 Jamin, C., Le Corre, R., Pers, J.P., Dueymes, M., Lydyard, P.M. and
Youinou, P. (1997) Int. Immunol. 9, 1001Ð1009
37 Knight, K.L. and Becker, R.S. (1990) Cell 60, 963Ð970
38 Pospisil, R., Fitts, M.G. and Mage, R.G. (1996) J. Exp. Med. 184,
1279Ð1284
39 Biancone, L., Bowen, M.A., Lim, A., Aruffo, A., Andres, G. and
Stamenkovic, I. (1996) J. Exp. Med. 184, 811Ð819
40 Bikah, G., Carey, J., Ciallela, J.R., Tarakhovsky, A. and Bondada, S. (1996)
Science 274, 1906Ð1909
41 Cerutti, A., Trentin, L., Zambello, R. et al. (1996) J. Immunol. 157, 1854Ð1862
42 Caligaris-Cappio, F. (1996) Blood 87, 2615Ð2620
43 Lalor, P.A., Herzenberg, L.A., Adams, S. and Stall, A.M. (1989) Eur. J.
Immunol. 19, 507Ð513
44 Uckun, F.M., Burkhardt, A.L., Jarvist, L. et al. (1993) J. Biol. Chem. 268,
21172Ð21184
45 Murakami, M. and Honjo, T. (1995) Immunol. Today 16, 534Ð539
46 Huang, C.A., Henry, C., Jacomini, J., Imanishi-Kari, T. and Wortis, H.H.
(1996) Eur. J. Immunol. 26, 2537Ð2540
47 Antin, J.H., Ault, K.A., Rappeport, J.M. and Smith, B.R. (1987) J. Clin.
Invest. 80, 325Ð332
48 Linton, P.I., Lo, D., Lai, L., Thorbecke, G.J. and Klinman, N.R. (1992) Eur.
J. Immunol. 22, 1293Ð1297
49 Pers, J.O., Jamin, C., Le Corre, R., Lydyard, P.M. and Youinou, P. (1998)
Eur. J. Immunol. 28, 4170Ð4176
50 Caligaris-Cappio, F., Riva, M., Tesio, L., Schena, M., Gaidano, G.L. and
Bergui, L. (1989) Blood 73, 1259Ð1263
51 Holder, M.J., Abbot, S.D., Milner, A.E. et al. (1993) Int. Immunol. 5,
1059Ð1066
52 Jamin, C., Magadur, G., Lamour, A. et al. (1991) Immunol. Lett. 31, 79Ð84
53 F�rster, I., Gu, H. and Rajewsky, K. (1988) EMBO J. 7, 3693Ð3703
54 Cai, J., Humphries, C., Richardson, A. and Tucker, P.W. (1992) J. Exp.
Med. 176, 1073Ð1081
55 Fischer, M., Klein, U. and K�ppers, R. (1997) J. Clin. Invest. 100,
1667Ð1676
56 Mageed, R.A., MacKenzie, L.E., Stevenson, F.K. et al. (1991) J. Exp. Med.
174, 109Ð113
57 Tarakhovsky, A., Kanner, S.B., Hombach, J. et al. (1995) Science 269, 535Ð537
58 Karras, J.G., Wang, S., Huo, L., Howard, R.G., Frank, D.A. and
Rothstein, T.L. (1997) J. Exp. Med. 185, 1035Ð1042
59 Tarakhovsky, A. (1997) J. Exp. Med. 185, 981Ð984
60 Pospisil, R. and Mage, R.G. (1998) Immunol. Today 19, 106Ð108
Why not recommend Immunology Today toyour librarian?
As well as the monthly issues, the library subscription to ITincludes a hardbound annual compendium. This provides apermanent reference source and contains the annual indexesof subjects and authors.