5
forum Forum: lymphocyte lifespans The simple question 'what is the lifespan of a typical lymphocyte' has proved to be far from easy to answer. First, it depends on the criteria used to define 'typical', and, even more so, on the definition of 'lifespan'. Even when these terms of reference are agreed upon, provid- ing a level playing field, it is almost certain that no two groups will play to exactly the same rules. Exper- imental approaches, timing aad type of measurement, species and age of animals, and environmental conditions, will vary markedly. As a result, the subject has become rather contentious in recent times. This Forum was commissioned to bring together short ar- ticles and comments from some of the leading figures in the field. Encouragingly, there is more agreement than disagreement, and it appears that a unifying principle for the study and understanding of lymphocyte life- spans is beginning to emerge. Lymphocyte lifespans: homeostasis, selection and competition Ant6nio A. Freitas and Bencdita B. Rocha As for any other organ or tissue of a multicellular organism, the immune system is under homeostatic c.-mtrrd cff coil nurnhor~ Frnm early i, ,4 .... I,-,p~,~n~ ,,,-, . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . d iil ~ i~1~ ill,ilL ~ until the adult stage, lymphocyte populations increase in size; in adults, the total number is constant. Homeostasis The sizes of T- and B-cell populations are main- tained independently. A similar number of mature B cells are found in normal, thymectomized and athymic mice, and in mice that lack T cells due to the deletion of T-cell receptor (TCR) genes by homologous recom- binarion (also known as TCR knockout mice)L In mice that lack B cells (mlgM knockout), the number of T cells is similar to normal mice-'. Within the peripheral compartment, the total num- ber of T cells is independent of cellular input. In mice transplanted with up to 50 thymus lobes, the total T- cell pool does not increase in sizeL Athymic nude mice injected with different numbers of T cells reconstitute their peripheral compartment to a similar ieveP. The total number of T cells is also independent of the input of CD4 + or CD8 + lymphocytes. In the absence of either the CD4 + or CD8 + T-cell subset, cell loss can be compensated by the remaining cellular subset, and the total number of T cells remains similar to that of nor- mal mice: this was shown by reconstitution of athymic mice with purified T-cell populations followed by anti- © 1993. Elsevier Science Publishers CD4 or anti-CD8 antibody treatment 4, and the analv- sis of either [[]z-microglobulin knockout micC, MH'C ,-I.-,c~ lI b,-,,,,--hoD t ,.,.,i,-.,~ ~,-~A ("i'~A b~b~,.~ " - _,~.:,o x~ ~H-..a'~r~ xHz~...~ ,atl~ x.~L.-1 ~x[t,on,.r~,.Jtat mlce . In mice transgenic for complete Ig or TCR mol- ecules, the numbers of mature peripheral lymphocytes, the vast majority of which bear transgenic molecules, does not differ greatly from the number of cells in nor- mal mice. Thus, control of lymphocyte numbers is probably independent of cell specificity. It is con- ditioned by circulating hormones, growth factors and lymphocyte products (reviewed in Ref. 8). Lymphocyte lifespans The homeostatic control of cell numbers implies a kinetic steady state where cell production equals cell loss. The immune system must, however, adapt to changes in environment through selection of appropri- ate clonal specificities. Selection of new specificities in a'.l lymphoid compartments depends on the renewal rate of cells in that compartment. Renewal rates J ...... A ~-t| J ..... : . . . . ..,I ~1~- L - I (.IC[,.)t~IIH Uil I.•II l~tuuu~,tIul| allu ucdtll WltDln, as well as cell input and output to and from other cellular com- partments. All these parameters are reflected in the time that a cell survives inside a certain compartment, that is, in lymphocyte lifespans. Definitions of lymphocyte lifespans vary according to different conceptual and experimental systems. These differences can be summarized by the question: Ltd. UK. 016,-~699193/$0e~:00 Immunology Today 25 Vol 14 No. I 1993

Lymphocyte lifespans: homeostasis, selection and competition

Embed Size (px)

Citation preview

forum

Forum: lymphocyte lifespans The simple question 'what is the lifespan of a typical lymphocyte' has proved to be far from easy to answer. First, it depends on the criteria used to define 'typical', and, even more so, on the definition of 'lifespan'. Even when these terms of reference are agreed upon, provid- ing a level playing field, it is almost certain that no two groups will play to exactly the same rules. Exper- imental approaches, timing aad type of measurement, species and age of animals, and environmental conditions, will vary markedly. As a result, the subject has become rather contentious in recent times. This Forum was commissioned to bring together short ar- ticles and comments from some of the leading figures in the field. Encouragingly, there is more agreement than disagreement, and it appears that a unifying principle for the study and understanding of lymphocyte life- spans is beginning to emerge.

Lymphocyte lifespans: homeostasis, selection and competition

Ant6nio A. Freitas and Bencdita B. Rocha

As for any other organ or tissue of a multicellular organism, the immune system is under homeostatic c.-mtrrd cff coil nurnhor~ Frnm early i , ,4 .... I,-,p~,~n~ ,,,-, . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . d i i l ~ i ~ 1 ~ i l l , i l L ~

until the adult stage, lymphocyte populations increase in size; in adults, the total number is constant.

Homeostasis The sizes of T- and B-cell populations are main-

tained independently. A similar number of mature B cells are found in normal, thymectomized and athymic mice, and in mice that lack T cells due to the deletion of T-cell receptor (TCR) genes by homologous recom- binarion (also known as TCR knockout mice)L In mice that lack B cells (mlgM knockout), the number of T cells is similar to normal mice-'.

Within the peripheral compartment, the total num- ber of T cells is independent of cellular input. In mice transplanted with up to 50 thymus lobes, the total T- cell pool does not increase in sizeL Athymic nude mice injected with different numbers of T cells reconstitute their peripheral compartment to a similar ieveP. The total number of T cells is also independent of the input of CD4 + or CD8 + lymphocytes. In the absence of either the CD4 + or CD8 + T-cell subset, cell loss can be compensated by the remaining cellular subset, and the total number of T cells remains similar to that of nor- mal mice: this was shown by reconstitution of athymic mice with purified T-cell populations followed by anti-

© 1993. E l s e v i e r S c i e n c e P u b l i s h e r s

CD4 or anti-CD8 antibody treatment 4, and the analv- sis of either [[]z-microglobulin knockout micC, MH'C , - I . - ,c~ l I b , - , , , , - - h o D t ,. , . ,i ,-.,~ ~,-~A ( " i ' ~ A b ~ b ~ , . ~ " - • _ , ~ . : , o x ~ ~ H - . . a ' ~ r ~ x H z ~ . . . ~ , a t l ~ x . ~ L . - 1 ~ x [ t , o n , . r ~ , . J t a t m l c e .

In mice transgenic for complete Ig or TCR mol- ecules, the numbers of mature peripheral lymphocytes, the vast majority of which bear transgenic molecules, does not differ greatly from the number of cells in nor- mal mice. Thus, control of lymphocyte numbers is probably independent of cell specificity. It is con- ditioned by circulating hormones, growth factors and lymphocyte products (reviewed in Ref. 8).

Lymphocyte lifespans The homeostatic control of cell numbers implies a

kinetic steady state where cell production equals cell loss. The immune system must, however, adapt to changes in environment through selection of appropri- ate clonal specificities. Selection of new specificities in a'.l lymphoid compartments depends on the renewal rate of cells in that compartment. Renewal rates J . . . . . . A ~ - t | J . . . . . : . . . . ..,I ~ 1 ~ - L - I • (.IC[,.)t~IIH U i l I.•II l ~ t uuu~ , t I u l | a l l u u c d t l l W l t D l n , as well as

cell input and output to and from other cellular com- partments. All these parameters are reflected in the time that a cell survives inside a certain compartment, that is, in lymphocyte lifespans.

Definitions of lymphocyte lifespans vary according to different conceptual and experimental systems. These differences can be summarized by the question: L t d . U K . 016,-~699193/$0e~:00

Immunology Today 25 Vol 14 No. I 1993

forum

do we mean that a cell dies at the end of its lifespan, or that it forms two cells?

These definitions have different physiological signifi- cance and limitations. The first does not consider that a clonat specificity may persist in vivo through continu- ous 'shqrt-lived" dividing cells. It does not distinguish clonal elimination from clonal expansion. The second does not consider that cells may change after cell div- ision. These changes may modify the behaviour of a lymphocyte in response to the same stimulation.

Table 1 summarizes three decades of research, plesented according to the different experimental approaches employed to define lifcspans ~-~'.

Rate of cell division The concept that a cell becomes two cells is the most

commonly used approach to study the lifespan of lym- phocytes. The incorporation of labelled DNA precur- sors, namely rritiated thymidine I~H]TdR or bromo- deo.'q'uridine (BrdU), is taken as the index of cell division. ]'he m vWo rate of accumulation (or clearance) of labelled cells is used to quantif3" the fraction of short- and !ong-lk ed cells ~--''.

There is widespread agreement on the high rate of lymphocyte production and turnover in the bone mar- row and thymus ~s-'~'~s and on the fact that peripheral mature lymphocytes contain bo~h short-lived and long- lived pepulations. However, the fraction of each cell type varies in different studies. These variations are, in part, due to the different cell types analysed (for ex- ample, total lymphoid populations or small l~mphocytes) and the different protocols of administration of DNA precursors employed (Table 1 ). Considering only stud- ies on the accumulation or clearance of labelled cells in the spleen, and excluding those involving surgical manipulation, which induces stress, two different views have emerged. One view, based on reports which

salvage pathway 4~ and thus may fail to label mature lymphocytes in which the utilization of the de novo pathway predominates 4°. Progressive incorporation of exogenous nucleotides induces cytotoxic effects due to changes of the intracellular poo!s of endogenous nucleotides, mimics the effects of cytostatic agents, and leads to the selective ehmination of cycling cells and their progeny 42"43.

We conclude that these methods can provide no more than minimal estimates of cell turnover.

Persistence after arrest of cell production Cycling cells can be selectively eliminated in vivo by

administration of cytostatic drugs. Cell production is blocked and resting cells persist after treatment. The extent of cell persistence has been used as a definition of iifespan. In contrast to methods employing the incorporation of DNA precursors, which label cycling cells exclusively through the salvage pathway, the use of cytostatic drugs leads to the elimination of all cycling cells, irrespective of the metabolic pathways of DNA synthesis.

Hydroxyurea, a commonly used cytostatic drug, has a transient effect in vivo; it causes depletion of 40-50% of peripheral mature lymphocytes within three days of administration -'4"-'s. Similar results have been obtained by treating mice transgenic for the HSV-1 thymidine kinase (tk) gene with the antiherpetic drug ganciclovir, a nucleoside analogue which is incor- porated by cells in the S phase of the cell cycle -''. The ItSV-1 tk transgene is under the control of the lg ~¢ chain promoter and p. enhancer elements; this ensures its exclusive expression in B and T cells. Ganciclovir administration selectively kills all dividing lymphoid cells and induces the disappearance of 65% of T cel!s and 90% of B cells within seven days -'~.

Therefore studies following cell persistence after show that 30--50% of cells were labelled after 3-7 cvtostatic treatment are enn~icrPnr ~irh rh,~ ~,i .... rh.,t

J . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ~ 1 ~ . , ~ . . L . , ~

days ~]''s''6-'°2~, claims that the majority of peripheral lymphocytes have a relatively short lifespan 21. The sec- ond view, based on the findings that only 20--30% of splenocytes were labelled after a time period of 2-3 weeks, considers that most (70%) mature lymphocytes are stable cellular populations with lifespans longer than 2-4 weeks 13a-qg. These contrasting results were obtained using different protocols of administration of DNA prec-,rsors, and reflect the limitations of the expenmema, approaches (reviewed in Refs 8 and 2i). These limitations include difficulties in ensuring ef- ficmnt in vwo labelling of all dividing cells, and the potential toxic effects of exogenous DNA precursors.

Lymphoid organs are mixtures of cells with different cycling times, dividing asynchronously. Studies on the accumulation of labelled cells require that the level of exogenous DNA precursors (which are rapidly cleared in vivo) is sufficient to label all DNA synthesizing cells, and to discriminate the progeny of such cells, as the amount of incorporated DNA precursor diminishes with cell division. The mechanisms involved in the incor- poration and processing of exogenous nucle'otides are complex, imply competition with endogenou~ precur-- sot pools and vary according to cell type 39"4°. Exogenous nucleotides are incorporated through the

most lymphoid cells have a short lifespan. Never- theless, cell deletion following cytostasis may be due to nonselective toxic effects. Although we have not de- tected toxicity to noncycling cells in the short sched- ules of hydroxyurea administration employed, this drug eliminates nonlymphoid proliferating cells and may induce general effects that could affect cell survival. The recent finding that ganciclovir separately affects lymphoid populations in the bone marrow without altering the numbers of nonlymphoid precursors (authors' unpublished observations), together with the observations that its action can be fully reversed in vitro by thymidine 44, seems to exclude nonselective effects.

In general, these approaches suggest that continuous cell production is required to m~intain a stable popu- lazion size for both B and T cells. These methods do not discriminate between cell input from precursor pools and birth rate at the periphery.

Persistence after cell transfer Persistence of mature cells bearing a donor-specific

marker after transfer into histocompatible hosts has been used to define lifespans. Since mature donor cells cannot be renewed from the precursor compartments

Immunology Today 26 Vol. 14 No. 1 I993

forum

Table 1. Lymphocyte lifespans - results using different experimental strategies

Animal Experimental approach Surgery Organ Lymphocytes Fraction of cells/ Ref. studied lifespan

(a) Rate of cell division

Rat [~H]TdR labelling Yes TDL small 30%/2 weeks ') [~H]TdR clearing Yes TDL small 13',612 weeks

Rat [~H]TdR labelling No Blood small 30%/5 days 10 ['H]TdR clearing No Blood small 50%/2 weeks

Rat ['HITdR labelling No SPL small 60%/1 week 11 [3H]TdR clearing No SPL small 75%/2 weeks

Rat ['H]TdR labelling Yes TDL B 45%/1 week 12 T 12%/1 week small 3-11%/1 week

Mouse [~H]TdR labelling Yes TDL small B 30%/2 weeks - 80%/6 weeks 13 small T 15%/2 weeks - 38%/6 weeks

Mouse [~H]TdR labelling No SPL small 20%/1 week 14 [3H]TdR clearing No SPI. small 20%/3 weeks

Mouse [3H]TdR labelling No SPL B 25%/4 days 15 T 7%/4 days

Guinea Pig [~H]TdR labelling No SPL B 25..-45%/3 days 16 Rat BrdU labelling No SPL B 20%/5 days 17 Mouse BrdU labelling No SPL B 15 %/8 days 18,19

BrdU clearing No SPL B 30%/4 weeks Mouse BrdC labelling No SPL all 35%/3 days 20 Mouse BrdU labelling No SPL B 40%/3 days 21

T 30%/3 days

(b) Persistence after arrest of cell production

Rat [~H]TdR killing Yes TDL B >50%/2 days 22 Mouse ~Sr aplasia No SPI, B 50%/3-4 clays 23 Mouse HU killing No SPL B 40-50%/3 days 24 Mouse HU kilhng No SPL; LN T 30-50%/3 days 25 Mouse HU killing No SPL B and T 70%/5 days 26 Mouse Tk obliteration minor SPL B 90%/7 days 27

T 65%17 days

(c) Persistence after cell transfer

Mouse Cell transfer Yes (B-mice hosts)

Mouse Cell transfer No (allotype markers)

Mouse Cell transfer No (LPSr; adult hosts)

2nd CelJ transfer No Mouse Cell transfer No

IThy 1 marker; nu-nu hosts) Mouse Cell transfer

I I~I / " ' / '~T I . / V ; A k ~ - ~ : ~.

Mouse Cell transfer (allotype markers)

Mouse Cell transfer (LPSr; newborn hosts)

Mouse Cell transfer (SCID hosts)

SPL

SPL

SPL LN Blood SPL SPL;LN

No SP~, ; . . . . . . . . . . /

No SPL;LN

No SPL

No SPL;LN

T Persistence

-0°6/ B ,, J 6 days

B 70-80%i 7-1a days B 50%/4-6 days B 30%• 7 days B Persistence/7 days T Persister~ce

B 60%/10 days

B 80%/2 weeks

B Persistence

B and T Persistence

28

29

30-32

33

34

35

36

37

SPL: spleen; LN: lymph node; TDL: thoracic duct lymph; LPSr: lipopolysacchande reactivity.

Immunology Today 27 vot 14 No. 1 1993

forum

present in the new host, this approach can establish the role of bone marrow or thymus in the turnover of mature lymphocytes. Clonal persistence after transfer ,.an be due to noncycling long-lived populations or to cycling cells capable of self-renewal in the periphery.

In it, tact or irradiated adult hosts, donor B cells decay rapid!y. By 7-10 days after transfer, 60-80% of the cells recovered initially at day 1, have disap- peared 2~-~2"~4". These results suggest that maintenance of peripheral B-cell pools requires the contin:mus pro- duction and export from the bone marrow. The remaining B cells are long-lived populations: they can- not be eliminated by cytostatic drt:~s and persist with- out decay in seconda~, transfers;L

Transferred mature peripheral T cells expand and/or persist zs'~. These results, together with studies on the effects of adult or neonatal thymectomy, show that stable peripheral T-cell numbers can be maintained in the absence of the thvmic precursor pool by continuous cell division at the periphery.

LymphoQ~te renewal rates Clearly, evaluation of the lymphocyte renewal rates

cannot be based on a single experimental strategy and must take into consideration estimates of production and export of cells from the bone marrow and thy- m i l s js2|'23"~''~'4:''4°. On the basis of our studies using four different approaches, and the support of other obser- vations, we suggest that about 30--40% of peripheral immunocompetent B and T cells are renewed every 3 days, and that most B cells are renewed within 10 days ~ 1.202124"-3 ¢'.

The mechanism of cell renewal differs for B and T cells. Thus, while B cells are renewed through continu- ous production and export from the bone marrow ~, T cells are mainly renewed by cell generation at the periphery :s,'~.

Lifespan is not an intrinsic property of the cell Cell transfer experiments have shown that lympho-

cyte survival varies with environmental influences. Thus, while in adult hosts most of the transferred B cells are lost shortly after transfer, in newborn hosts B cells transferre-I from adult donor mice can expand at rhe same rate as host cells, and persist for 3-4 weeks, that is, until these mice become aduh% Similarly in immunodeficient SC|D adult hosts, donor B cells expand and can persist up to six months after transfer ~'.

B-cell and T-cell survival is influenced by selection. Transter of mature B cells, if followed immediately by appropriate antigenic challenge, results in the expan- sion and survival of donor cells 4~. Studies on the differ- ential decay of small or large activated B cells have led us to suggest that B-cell persistence is an acquired property of lymphocytes which requires a pre-acti- ration step ~. The finding of a modified V H-gene family expression among long-lived B cells further demon- strates that the life-span of B cells is determined by selection (A-C. Viale et al., submitted). Selection for persistence is likely to occur in the germinal centers 48 and may involve activation steps which prevent apop- tosis through the induction of genes, such as bcl-2 (Refs 49, 50).

Selection of T-cell specificities also occurs at multiple steps of T-cell differentiation. The T-cell repertoire is shaped in the thymus s~ and further selection of T-cell specificities occur in the periphery 5-'-53 through the expansion of mature T cells. The latter step consiaer- ably modifies the representation of T-cell specificities initially selected in the thymus.

The role of the thymus output in the turnover of mature T-cell populations in adult mice has yet to be established. Kinetic studies and sequential T-ceil trans- fers into athymic hosts (authors' unpublished studies) show that, in adult mice the peripheral T-cell pool is permeable, allowing the incorporation and expansion of recent thymic migrants -'~.-'s.

Thu.-, lymphocyte lifespan is not an intrinsic prop- erty of a cell. Rather, lymphocytes, at different stages of differentiation have a different probability rate of survival which is modulated by their interactions with the envir,-,nment.

Cellular competition In an immune system where there is a continuous

renewal and selection of immunocompetent cells and where the total number of cells is under strict control, peripheral B- and T-cell repertoires are shaped by the differential ability of lymphocytes to survive. Since the total number of ,.ells is limited, each newly produced lymphocyte can only establish itself upon loss of other cells, and has to compete with other newly produced or resident cells for survival and/or differentiation. New clones may replace a less efficient variant, pro- vided that they have a selective advantage.

Selection is a- a _~___,. mculateu by ,.,t,l,~,,y distributed recep- tors and will depend on the affinity and concentration of existing iigands, as well as on the presence of growth and differentiating factors. The immune system shows, therefore, a competitive selection ~haviour that has been described for ecological systems 54.5s.

Ant6nio Freitas is at the Unit~ d'lmmunobiologie, lnstitut Pasteur, Paris, France; Benedita Rocha is at the INSERM, U 345, CHU, Necker, Paris, France.

We would like te thank Drs Alf Grandien, Delphine Guy- Grand and Caroline Tucek for discussions, suggestions and reviewing of the manuscript; Anne-Claire Viale for sugges- tions and for unpublished results.

References 1 Mombaerts, P., Clarke, A.R., Ruduicki, M.A. et al (1992) Nature 360, 225-231 2 Kitamura, D., Roes, J., Kuhn, P. and Rajewsky, K. (1991) Nature 350, 423-426 3 Wallis, V.J., Leuchars, E., Chauduri, H. and Davies, A.J.S. (1979) Immunology 38, 163-175 4 Rocha, B., Dautigny, N. and Pereira, P. (1989) Eur. J. lmmunol. 19, 905-911 5 Ziiistra , M., Bix, M., Simister, N.E. et al. (1990) Nature 344, 742-746 6 Cosgrove, D., Gray, D., Dierich, A. et al. (1991) Cell 66, 1051-1066 7 Rahemtulla, A., Tung-Leung, W.P., Schilham, M.W. et al. (1991) Nature 353, 180-184 8 Frekas, A.A. and Rocha, B. in Autoimmunity (Coutinho,

Immunology Today 28 rot 14 No. I I993

forum

A. and Kazatchkine, M., eds), John Wiley (in press) 9 Caffrey, R.W., Rieke, \'v.O. and Everett, N.B. (1962) Acta Haemata 28, 145-154 I0 Robinson, S.H., B:echer, G., Lourie, I.S. and Hale},, J.E. (1965) Blood 26, 21~1 11 Everett, N.B. :.nd Tyler, R.W. (1967)Int. Rev. Cytol. 22, 205-237 12 Howard, J. (1972) I. Exp. Med. 135, 185-197 13 Sprent, J. and Basten, A. (i973) Cell. Immunol. 7, 40-59 14 Ropke, C. and Everett, N.B. (1975) Anat. Rec. 183, 83-94 15 Press, O.W., Rosse, C. and Clagett, J. (1977) Cell. Immunoi. 33, 114-124 16 Rosse, C., Cole, S.B., Appleton, C, Press, O.W. and Clagett, J. (1978) Cell. Immunol. 37, 254-262 17 Gray, D. (1988)J. Exp. Med. 167, 805-816 18 Forster, I., Vieira, P. and Raiewsky, K. (1989) Int. Immunol. 1,321-331 19 Forster, I. and Rajewsky, K. (1990) Proc. Natl Acad. Sci. USA 87, 4781-4786 20 Crippen, T.L. and Jones, I.M. (1989) Cell Tissue Kinetics 22, 203-212 21 Rocha, B., Penit, C., Baron, C. etal. (!990) Eur. J. Immunol. 20, 1697-1708 22 Strober, S. (1972)J. Exp. Med. 136, 851-861 23 Rozing, J., Buurman, W.A. and Benner, R. (1976) Cell. lmmunol. 24, 79-90 24 Freitas, A.A., Rocha, B., Forni, L. and Coutinho, A. (1982) ]. lmmunt, l. 128, 54-60 25 Rocha, B., Freitas, A.A. and Coutinho, A. (1983) J. lmmunol. 131, 2158-2164 26 Levy, M. (1985) Cell. Immunol. 96, 290-300 27 Heyman, R.A., Borreli, E., Lesley, J. et al. (1989) J. lmmunol. 86, 2698-2702 28 Miller, R.A. and Stutman, O. (1984)J. lmmunol. 133, 2925-2932 29 Park, Y-H., Yoshida, Y., Uchino, H., Inaba, M.M. and Masuda, T. (1985) Cell. lmmunol. 93, 58-67 30 Freitas, A.A. and Coutinho, A. (t981)J. Exp. Med. 154, 994-~vv 31 Freitas, A.A., Rocha, B. and C,~utinho, A. (1986) hnmunol. Rev. 91, 5-37

32 Freitas, A.A., Rocha, B. and Coutinho, A. (1986; J. Immunol. 136, 466-469 33 Rocha, B. (1987)/. lmnuotol. 139, 365-37 ~ 34 Udhayakumar, V.,Goud, S.N. andSubara,,~; 19s~ Eur. J. Immunol. 18, 1593-1599 35 Goroff, D.K. and Finkelman, F.D. (1989) 7th Int. Cong. hnmuno!. (abstr. 47-4), p. 262, Gustav Fisher Verlag 36 Thomas-Vaslin, V. and Freitas, A.A. {1989) Int. hnmunol. I, 237-246 37 Sprent, J., Schaefer, M., Hurd, M., Surh, D. and Ron, Y. (1991)]. Exp. Med. 174, 717-728 38 Opstelten. D. and Osmond, D. (1983) ]. Immunol. 131, 2635-2640 39 Reichard, P. (1988) Annu. Rev. Biochem. 57, 349-374 40 Cohen, A., Barankiewicz, J., Lederman, H.M. and Gelfand, E.W. (1983)J. Biol. Chem. 258. 12334-12340 41 Haaskjold, E., Refsum, S.B., Bjerknes, R. and Paulsen, T.O. (1988) Cell Tissue Kinetics 21,389-401 42 Bianchi, V., Pontis, E. and Reichard, P. (1986) Pro~. Natl Acad. Sci. USA 83, 986-990 43 Martin, D.W. and Gelfand, E.W. ! 1981 ) Atom. Rev. Biochem. 50, 845-870 44 Oliver, S., Bubley, G. and Crumpacker, C. t1985) Virology 145, 84-93 45 Brahim, F. and Osmond, D. (1970) Anat. Rec. 168, 139 46 Scollay, R.G., Butcher, E.C. and Weissman, I. (1980) Eur. ]. Immunol. 10, 210-218 47 Moiler, G. (1968)J. Exp. Med. 127, 291 48 MacLennan, I.C.M., Liu, Y-J., Oldfield, S., Zhang, J. and Lane, P.J.L. (1990) Curt. Top. Microhiol. Immu,ml. 159, 537 49 McDonnel, T.J., Nunez, G., Platt, F.M. et al. !1990) Mol. Cell. Biol. 10, 1901-1907 50 Strasser, A., Harris, A. and Cory, S. (1991) Cell67, 889-899 51 Huesman, M., Scott, B., Kisielow, P. and yon Boehmer, H. (1991) Cell66, 533--540 52 Rocha, B. and yon Boehmer, H. ( 1991 ) Science 251, 1225-1228 53 Rocha, B. (1992)Res. Immuno!. 143,299-303 54 Eigen, M. and Winkler, R. t1975! Das Spiel. Natur~esetze Steuern den Zu[all, R. Piper and Co., Ve-lag 55 May, R.M. (1976) Nature 261,459-467

The dynamic relationship between B-cell populations in adults Ian MacLennan and Eric Chan

B lymphocytes are produced throughout life by pri- mary B-cell production from haemopoietic cells in the mzrrow and through antigen-driven proliferation in secondary lymphoid tissues. Only a small proportion of these newly produced ceils have more than a brief lifespan as B cells (Table 1). The minority that sur- vive, differentiate to become part of the relatively stable pools of peripheral B cells. In rodents, unless the lymphocytes of these peripheral B-cell pools are activated by antigen, they have an estimated lifespan

© 1993, Elsevier Science Pubhshvrs

ranging from three to a few weeks. Although these peripheral B cel!s constitute only a fraction of the B cells produced, they comfortably make up the ma- jority of B cells found in the body. Short-lived B cells appear to have a brief lifespan because they have failed to receive signals which would induce them to differentiate to become long-lived cells. Equa!~y, the survival of cells with a relatively greater lifespan may depend on their receiving regular signals without which they would die. [.td. UK. 01 (~--569919 :~/$06.0N

Immunology Today 29 Vol. 14 No. 1 1993