Organization and maintenance of ... - Wiley Online Library

Eur. J. Immunol. 2009. 39: 2095–2099

DOI 10.1002/eji.200939500

HIGHLIGHTS

Koji Tokoyoda1, Sandra Zehentmeier1, Hyun-Dong Chang1 and Andreas Radbruch1,2 1

2

Deutsches Rheumaforschungszentrum Berlin, Wissenschaftsgemeinschaft Leibniz, Charite´platz, Berlin, Germany Experimental Immunology, Department of Rheumatology and Clinical Immunology, Charite Universita¨tsmedizin Berlin, Charite´platz, Berlin, Germany

Immunological memory is still one of the enigmas of modern immunology. We poorly understand the generation of memory cells from their precursors, the lifestyle of memory cells or their maintenance, reactivation and termination. Here, we discuss the recent evidence suggesting that memory plasma cells, as defined in this review, and memory Th cells are maintained in the bone marrow, resting (in terms of proliferation) in survival niches organized by dedicated stroma cells, which control the homeostasis of immunological memory.

Maintenance of memory lymphocytes Some authors negate the existence of specialized memory cells at all, reserving the term ‘‘immunological memory’’ for the numeric amplification of specific lymphocytes [1, 2], and correctly pointing to the lack of distinctive parameters between long-lived effector lymphocytes and professional memory lymphocytes [2]. In part, this stems from the confusion as to what extent effector lymphocytes are maintained by chronic immune reactions, driven by residual antigen, as compared with ‘‘memory’’ in its strict sense, i.e. the ‘‘maintenance of information in the absence of effective antigenic instruction’’ [3]. Memory in this strict sense has been demonstrated for B lymphocytes, by experimentally switching their specificity, by targeted mutagenesis [4], for memory T cells, by deleting their ab T-cell receptor [5], and for long-lived plasma cells, which no longer respond to antigen, and rest in terms of proliferation. Although the definition regarding plasma cells may appear unconventional at first glance, we suggest that long-lived plasma cells could also be termed ‘‘memory’’ plasma cells [6–8]. Rather than being dependent on antigen, maintenance of memory lymphocytes has been shown to depend on cytokine signals, as reviewed in [9], with the general picture emerging that

Correspondence: Professor Andreas Radbruch e-mail: [email protected]

& 2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

CD8 memory T cells are maintained by IL-7 and IL-15 [10–13], CD4 memory cells by IL-7 [14], and memory plasma cells by APRIL and B-Lys [15]. The maintenance signal for memory B cells is less clear; it is not APRIL and/or B-Lys [15] but a, so far, unidentified signal, which acts via phospholipase Cg2 [16]. These memory-maintaining cytokines have been shown to be essential, since their blockade or removal leads to the elimination of established memory cells. Other signals may also be relevant. For example, for memory plasma cells, it has been shown that CXCL12, IL-6 and ligands of CD44 promote survival, at least in vitro [17, 18]. While some molecular signals for survival of memory lymphocytes have been identified, it remains enigmatic how the memory cells pick up the signals and how they exactly react to them. These questions are closely linked to the lifestyle of memory lymphocytes. Are they surveying the body in the quest for antigen, with a certain ‘‘half-life’’, slowly dividing to keep their numbers constant [19, 20], or are they residing and resting in distinct niches, which provide them with survival signals, either waiting to be reactivated by cells presenting them their antigen there, in the case of T lymphocytes, or secreting their antibodies, in the case of plasma cells?

Bone marrow stroma niches for memory plasma cells Plasma cells have been recognized as an independent type of memory cell only recently [7, 21], although it had been known

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for some time that plasma cells can be long-lived and maintained in the absence of B cells, their immediate precursors [22]. Already in 1972 it had been described that in the memory phase of an immune response, plasma cells are maintained mostly in the bone marrow, while a few are located in the spleen and lymph nodes [23]. In the bone marrow, plasma cells survive for time periods of more than 4 months, probably years, without DNA synthesis and cell division, i.e. resting in terms of cell cycling, but highly active in terms of protein synthesis, secreting several thousand antibodies per second [24]. It is apparent that survival of plasma cells in the bone marrow is dependent on the signals from their environment: when isolated from the bone marrow, or any other tissue, plasma cells rapidly die in vitro, within days [17, 25]. Their survival in vitro can be prolonged by a variety of signals [17], but nothing, not even stroma cell lines or ex vivo bone marrow, can substitute, so far, for the in vivo situation. Survival of memory plasma cells is thus conditional and depends on being in a dedicated plasma cell survival niche. A hallmark and organizer of this niche seems to be stroma cells expressing the chemokine CXCL12 [18]. Activated B lymphocytes and plasmablasts, the immediate precursors of plasma cells, express CXCR4, and migrate in response to gradients of CXCL12 [18, 26]. It is remarkable that plasma cells themselves are no longer migratory. In the bone marrow, plasma cells are located individually next to CXCL12-expressing stroma cells [27] and they respond to CXCL12 by prolonged survival [18]. This defines the CXCL12-expressing stroma cells as an essential component of the bone marrow plasma cell niche, suggests how plasmablasts are attracted by survival niches, and how they might compete with resident plasma cells for habitation of the niches [8]. It also defines that the CXCL12-expressing stroma cells are the organizers of plasma cell memory, limiting the numbers of plasma cells that can be maintained, and thus the overall concentration of serum antibodies. The frequency of CXCL12-expressing stroma cells, which also express VCAM1, is about 1% of total bone marrow cells. These CXCL12-expressing stroma cells also provide niches for early B-cell ontogeny [27]. Nevertheless, 1% is also the upper limit of the physiological frequency of plasma cells in bone marrow [28]. In this respect, it is remarkable, that most of the plasma cells individually colocalize with VCAM1+CXCL12+ stroma cells [27], the molecular basis of this restriction to monogamy being currently unclear. Niches for plasma cells have also been described for other tissues, in particular secondary lymphoid tissues [29]. It has been shown that long-lived plasma cells can also be maintained in inflamed tissue, over extended time periods, suggesting that such tissue provides niches for these cells as well [30]. Peripheral niches for plasma cells provide an elegant way to bring plasma cells close to the antigens they are specific for, and to provide high local concentrations of antibodies there. It is also an elegant way to contract the numbers of plasma cells after the acute immune reaction, when the inflamed tissue is regenerated and the plasma cells are no longer migratory and cannot move to other niches anymore [8].


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Bone marrow stroma niches for memory T helper lymphocytes From the analysis of bone marrow memory plasma cells it appears, that homeostasis of the plasma cell memory is regulated by dedicated stroma cells, providing temporary or stable survival niches. Is this a special case or is immunological memory organized this way in general? At first glance, it appears as if the reactive immunological memory of memory B and T lymphocytes is organized differently. B lymphocytes-expressing antibodies of switched isotype and somatically mutated antigenbinding sites, i.e. memory B lymphocytes are easily detectable in blood and secondary lymphoid organs [31], as are T lymphocytes-expressing markers indicating previous antigen-encounters, such as CD45RO in man [19] or elevated levels of CD44 in mice [32]. In the case of T lymphocytes, however, it has been argued previously that such markers also are expressed by effector T cells and do not necessarily define memory cells [2]. The distinction between memory-phenotype and effector-phenotype T cells is anyway fuzzy, since it has been shown that effector T cells can survive over extended time periods, even in the apparent absence of antigen [33, 34] and that ‘‘memory’’ and ‘‘effector’’ cells readily interconvert [33–35]. An additional layer of complexity and confusion is added by the apparent heterogeneity of CD4+ Th cells with a ‘‘memory phenotype’’, and their classification into central memory‘‘, ‘‘effector memory’’ and ‘‘follicular helper memory’’, according to the differential expression of chemokine receptors and adhesion molecules, such as CD62L, CCR7 or CXCR5, potentially attracting them into secondary lymphoid organs [36, 37]. It has been argued that these distinct T helper memory cell types provide help either to memory B cells and cytotoxic memory T cells in recall immune responses, or to effector cells, thereby orchestrating inflammation. How are these different types of memory T lymphocytes maintained? The essential role of IL-7 for CD4+ T helper memory cells, and IL-15 for CD8+ cytotoxic memory T cells, has become obvious from the genetic analysis of mice [20]. The current paradigm for memory T-cell maintenance is that memory T cells circulate the body in quest of cells presenting them their antigen or providing them with the survival signals IL-7 or IL-15. It remains unclear, however, when and where the memory T cells obtain the IL-7 and IL-15 signals, and how memory T-cell numbers are precisely regulated [38, 39]? Recently, we have addressed this question in murine model systems, by following the fate of antigen-specific T helper lymphocytes through acute immune reactions and the subsequent memory phases [40]. In immune responses to ovalbumin, LCMV peptide and NP-KLH, the specific Th cells expanded vigorously in the acute reaction, reaching peak cell numbers about 7 days after induction of the response. Thereafter, cell numbers dropped in the secondary lymphoid organs, i.e. the lymph nodes and spleen, declining quickly from day 14 to day 28, and slowly thereafter, in the memory phase. In the lymph nodes, spleen and blood, few specific Th cells remained detectable after 100–150 days, the end of the observation period. Surprisingly, however, between 28 and

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56 days after induction of the immune response, i.e. in the transition from the reactive phase of the immune reaction to the memory phase, when the numbers of specific T cells dropped in the periphery, we found a concomitant increase in their numbers in the bone marrow. After day 60, the numbers of specific memory cells in the bone marrow remained constant until the end of the observation period. A total of 10–20 % of the specific T lymphocytes generated in the immune reaction were maintained in the memory phase. At the end of the observation period, more than 90% of all specific lymphocytes were maintained in the bone marrow, as compared with the rest of the body. In the bone marrow, the specific T lymphocytes resided in contact with IL-7-expressing, VCAM1+ stroma cells, which comprise about 1% of the bone marrow cells, a similar percentage as for VCAM1+ CXCL12-expressing stroma cells, but a distinct cell population (see the section Plasma cell niches). In the memory phase of the immune reaction, no MHC class II-expressing cells are detectable in the vicinity of bone marrow memory Th cells. In the bone marrow, the specific T helper lymphocytes are switched off with respect to cell division and gene expression. They acquire a ‘‘memory phenotype’’, expressing CD44 highly, no CD62L, but Ly6C. These resting memory Th cells of the bone marrow can be quickly reactivated by antigenpresenting cells. They then express CD154 and cytokines within an hour and provide professional help to B lymphocytes for antibody affinity maturation. Of the Ly6C-expressing CD4+ T helper memory cells in the body, more than 80% are located in the bone marrow. These results strongly suggest that professional Th-cell memory resides in the bone marrow, maintained as resting cells by stroma niches defined by IL-7-expressing VCAM1+ stroma cells (Fig. 1). The numbers of memory Th cells are thus not controlled by homeostatic proliferation, but rather by the numbers of IL-7-expressing stroma cells of the bone marrow. These numbers are ‘‘predefined’’, in that they do not depend on the numbers of memory T cells. In WT and in T-cell deficient mice, IL-7-expressing VCAM1+ stroma cells comprise about 1% of the bone marrow cells [27]. IL-7-expressing stroma cells thus define the pool size of memory T helper lymphocytes. Predic-

Granulocyte April+?

Memory Th cell

Macrophage April+ ? IL6+/April+ Megakaryocyte

Plasmacell

Endothelium

Figure 1. Bone marrow stroma cells expressing VCAM1 and either IL-7 or CXCL12 organize niches for maintenance and survival of memory Th and memory plasma cells, respectively. These niches are in close proximity to the endothelial lining of small blood vessels of the bone marrow.


tably, adaptation of new specificities to the CD4+ T-cell memory will require competition between old and new memory cells, when there are no more free niches available.

A new view on the organization of immunological memory In light of our data, we believe that the origin and nature of those peripheral CD4+ helper T cells with a ‘‘memory phenotype’’ will have to be redefined, as will the relation between antigenpresenting cells and memory Th cells. Bone marrow memory T cells are obviously not scanning the body for cells presenting their antigen, rather, activated antigen-presenting cells must be scanning the bone marrow for reactive memory Th cells. Reactivated memory Th cells must be able to quickly reach the secondary lymphoid organs again, and mount a secondary immune reaction there. At least in our analysis, we did not detect secondary immune reactions in the bone marrow, although those may occur and have indeed been reported [41, 42]. We believe that our current picture on activation of the reactive immunological memory will change. With evidence available that memory plasma cells and memory Th cells are maintained in the bone marrow, resting in terms of proliferation, in niches organized by stroma cells and providing signals for survival, the question remains, how are memory CD8+ T cells and memory B cells maintained? The preferential homing of effector/memory-phenotype CD8+ T cells to bone marrow has been described [42–44], but those reports have stressed the ‘‘central memory’’ phenotype, motility and proliferation of CD8 cells in bone marrow. It remains unclear, whether in a true memory phase, CD8 memory T cells are maintained in the bone marrow as resting cells, as we have described for CD4+ memory T cells. For maintenance of memory B cells, a prominent role for the spleen has recently been suggested [45, 46], based on the loss of memory B cells in blood after splenectomy, and the observation that 20 times more smallpox-specific memory B cells reside in the spleen, as compared with the blood [45]. So, while memory plasma cells, memory Th cells and probably also cytotoxic memory T cells are maintained in the bone marrow, memory B cells may be maintained in the spleen, in niches as yet to be defined (Fig. 2). In view of the multitasking of memory B cells not only as antigensampling and presenting cells but also as reactive lymphocytes, this location, separate from the bone marrow, may make sense. The overall picture of immunological memory emerging from the data discussed here, is that memory is organized by mesenchymal stroma cells, which define the numbers of memory cells by providing niches for their survival as non-proliferating cells in the memory phase of immune responses, i.e. in the absence of antigen, which has been demonstrated clearly for memory Th cells and memory plasma cells. Obviously, knowing when and where to look for memory cells is a prerequisite for analyzing immunological memory in detail, and it seems we can now begin this endeavor.

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7 Slifka, M. K., Antia, R., Whitmire, J. K. and Ahmed, R., Humoral immunity due to long-lived plasma cells. Immunity 1998. 8: 363–372. 8 Radbruch, A., Muehlinghaus, G., Luger, E. O., Inamine, A., Smith, K. G., Dorner, T. and Hiepe, F., Competence and competition: the challenge of becoming a long-lived plasma cell. Nat. Rev. Immunol. 2006. 6: 741–750. 9 Schluns, K. S. and Lefrancois, L., Cytokine control of memory T-cell development and survival. Nat. Rev. Immunol. 2003. 3: 269–279. 10 Lodolce, J. P., Boone, D. L., Chai, S., Swain, R. E., Dassopoulos, T., Trettin, S. and Ma, A., IL-15 receptor maintains lymphoid homeostasis by supporting lymphocyte homing and proliferation. Immunity 1998. 9: 669–676. 11 Kennedy, M. K., Glaccum, M., Brown, S. N., Butz, E. A., Viney, J. L., Embers, M., Matsuki, N. et al., Reversible defects in natural killer and memory CD8 T cell lineages in interleukin 15-deficient mice. J. Exp. Med. 2000. 191: 771–780.

Figure 2. The concept of localized immunological memory, with niches for maintenance of memory plasma cells, memory T helper and, presumably, also cytotoxic memory T cells in bone marrow, and presumptive niches for memory B cells in the spleen [40, 46].

12 Becker, T. C., Wherry, E. J., Boone, D., Murali-Krishna, K., Antia, R., Ma, A. and Ahmed, R., Interleukin 15 is required for proliferative renewal of virus-specific memory CD8 T cells. J. Exp. Med. 2002. 195: 1541–1548. 13 Tan, J. T., Ernst, B., Kieper, W. C., LeRoy, E., Sprent, J. and Surh, C. D., Interleukin (IL)-15 and IL-7 jointly regulate homeostatic proliferation of memory phenotype CD81 cells but are not required for memory phenotype CD41 cells. J. Exp. Med. 2002. 195: 1523–1532. 14 Kondrack, R. M., Harbertson, J., Tan, J. T., McBreen, M. E., Surh, C. D. and

Acknowledgements: This work was supported by the Alexander von Humboldt Foundation through a stipend to K.T., by the International Max-Planck Research School through a stipend to S. Z., by the DFG through SFB421, SFB633 and SFB650, and by the European Commission through MUGEN and AUTOCURE. We thank Mir-Farzin Mashreghi and Christine Raulfs for critical reading of the manuscript.

Bradley, L. M., Interleukin 7 regulates the survival and generation of memory CD4 cells. J. Exp. Med. 2003. 198: 1797–1806. 15 Benson, M. J., Dillon, S. R., Castigli, E., Geha, R. S., Xu, S., Lam, K. P. and Noelle, R. J., Cutting edge: the dependence of plasma cells and independence of memory B cells on BAFF and APRIL. J. Immunol. 2008. 180: 3655–3659. 16 Hikida, M., Casola, S., Takahashi, N., Kaji, T., Takemori, T., Rajewsky, K. and Kurosaki, T., PLC-gamma2 is essential for formation and main-

Conflict of interest: The authors declare no financial or commercial conflict of interest.

tenance of memory B cells. J. Exp. Med. 2009. 206: 681–689. 17 Cassese, G., Arce, S., Hauser, A. E., Lehnert, K., Moewes, B., Mostarac, M., Muehlinghaus, G. et al., Plasma cell survival is mediated by synergistic effects of cytokines and adhesion-dependent signals. J. Immunol. 2003.

References 1 Zinkernagel, R. M., Bachmann, M. F., Kundig, T. M., Oehen, S., Pirchet, H. and Hengartner, H., On immunological memory. Annu. Rev. Immunol. 1996. 14: 333–367. 2 Bell, E. B. and Westermann, J., CD4 memory T cells on trial: immunological memory without a memory T cell. Trends Immunol. 2008. 29: 405–411. 3 Radbruch, A., Rajewsky, K., The cellular basis of B cell memory. In Frederick, W., Alt, T. H., Michael, S.N. (Ed.) The Molecular Biology of B Cells Elsevier Science, London 2004, pp. 247–259.

171: 1684–1690. 18 Hauser, A. E., Debes, G. F., Arce, S., Cassese, G., Hamann, A., Radbruch, A. and Manz, R. A., Chemotactic responsiveness toward ligands for CXCR3 and CXCR4 is regulated on plasma blasts during the time course of a memory immune response. J. Immunol. 2002. 169: 1277–1282. 19 Dutton, R. W., Bradley, L. M. and Swain, S. L., T cell memory. Annu. Rev. Immunol. 1998. 16: 201–223. 20 Surh, C. D. and Sprent, J., Homeostasis of naive and memory T cells. Immunity 2008. 29: 848–862. 21 Manz, R. A., Thiel, A. and Radbruch, A., Lifetime of plasma cells in the bone marrow. Nature 1997. 388: 133–134.

4 Maruyama, M., Lam, K. P. and Rajewsky, K., Memory B-cell persistence

22 Holt, P. G., Sedgwick, J. D., O’Leary, C., Krska, K. and Leivers, S., Long-

is independent of persisting immunizing antigen. Nature 2000. 407:

lived IgE- and IgG-secreting cells in rodents manifesting persistent

636–642.

antibody responses. Cell Immunol. 1984. 89: 281–289.

5 Polic, B., Kunkel, D., Scheffold, A. and Rajewsky, K., How alpha beta

23 McMillan, R., Longmire, R. L., Yelenosky, R., Lang, J. E., Heath, V. and

T cells deal with induced TCR alpha ablation. Proc. Natl. Acad. Sci. USA

Craddock, C. G., Immunoglobulin synthesis by human lymphoid tissues:

2001. 98: 8744–8749. 6 Manz, R. A., Lohning, M., Cassese, G., Thiel, A. and Radbruch, A., Survival of long-lived plasma cells is independent of antigen. Int. Immunol. 1998. 10: 1703–1711.


normal bone marrow as a major site of IgG production. J. Immunol. 1972. 109: 1386–1394. 24 Janossy, G., Gomez de la Concha, E., Luquetti, A., Snajdr, M. J., Waxdal, M. J. and Platts-Mills, T. A., T-cell regulation of immunoglobulin synthesis

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Eur. J. Immunol. 2009. 39: 2095–2099

and proliferation in pokeweed (Pa-1)-stimulated human lymphocyte cultures. Scand. J. Immunol. 1977. 6: 109–123. 25 Nossal, G. J., Szenberg, A., Ada, G. L. and Austin, C. M., Single cell studies on 19s antibody production. J. Exp. Med. 1964. 119: 485–502. 26 Hargreaves, D. C., Hyman, P. L., Lu, T. T., Ngo, V. N., Bidgol, A., Suzuki, G., Zou, Y. R. et al., A coordinated change in chemokine responsiveness guides plasma cell movements. J. Exp. Med. 2001. 194: 45–56. 27 Tokoyoda, K., Egawa, T., Sugiyama, T., Choi, B. I. and Nagasawa, T., Cellular niches controlling B lymphocyte behavior within bone marrow during development. Immunity 2004. 20: 707–718. 28 Terstappen, L. W., Johnsen, S., Segers-Nolten, I. M. and Loken, M. R., Identification and characterization of plasma cells in normal human bone marrow by high-resolution flow cytometry. Blood 1990. 76: 1739–1747. 29 Mohr, E., Serre, K., Manz, R. A., Cunningham, A. F., Khan, M., Hardie, D. L., Bird, R. and MacLennan, I. C., Dendritic cells and monocyte/macrophages that create the IL-6/APRIL-rich lymph node microenvironments where plasmablasts mature. J. Immunol. 2009. 182: 2113–2123. 30 Cassese, G., Lindenau, S., de Boer, B., Arce, S., Hauser, A., Riemekasten, G., Berek, C. et al., Inflamed kidneys of NZB / W mice are a major site for the homeostasis of plasma cells. Eur. J. Immunol. 2001. 31: 2726–2732. 31 Tarlinton, D., B-cell memory: are subsets necessary? Nat. Rev. Immunol. 2006. 6: 785–790. 32 Budd, R. C., Cerottini, J. C., Horvath, C., Bron, C., Pedrazzini, T., Howe, R. C. and MacDonald, H. R., Distinction of virgin and memory T lymphocytes. Stable acquisition of the Pgp-1 glycoprotein concomitant with antigenic stimulation. J. Immunol. 1987. 138: 3120–3129. 33 Lohning, M., Hegazy, A. N., Pinschewer, D. D., Busse, D., Lang, K. S., Hofer, T., Radbruch, A. et al., Long-lived virus-reactive memory T cells generated from purified cytokine-secreting T helper type 1 and type 2 effectors. J. Exp. Med. 2008. 205: 53–61.

38 Blair, D. A. and Lefrancois, L., Increased competition for antigen during priming negatively impacts the generation of memory CD4 T cells. Proc. Natl. Acad. Sci. USA 2007. 104: 15045–15050. 39 Hataye, J., Moon, J. J., Khoruts, A., Reilly, C. and Jenkins, M. K., Naive and memory CD41 T cell survival controlled by clonal abundance. Science 2006. 312: 114–116. 40 Tokoyoda, K., Zehentmeier, S., Hegazy, A. N., Albrecht, I., Gru¨n, J. R., Lo¨hning, M., Radbruch, A., Professional memory CD41 T lymphocytes preferentially reside and rest in the bone marrow. Immunity 2009. 30: 721–730. 41 Sapoznikov, A., Pewzner-Jung, Y., Kalchenko, V., Krauthgamer, R., Shachar, I. and Jung, S., Perivascular clusters of dendritic cells provide critical survival signals to B cells in bone marrow niches. Nat. Immunol. 2008. 9: 388–395. 42 Feuerer, M., Beckhove, P., Garbi, N., Mahnke, Y., Limmer, A., Hommel, M., Hammerling, G. J. et al., Bone marrow as a priming site for T-cell responses to blood-borne antigen. Nat. Med. 2003. 9: 1151–1157. 43 Mazo, I. B., Honczarenko, M., Leung, H., Cavanagh, L. L., Bonasio, R., Weninger, W., Engelke, K. et al., Bone marrow is a major reservoir and site of recruitment for central memory CD81 T cells. Immunity 2005. 22: 259–270. 44 Becker, T. C., Coley, S. M., Wherry, E. J. and Ahmed, R., Bone marrow is a preferred site for homeostatic proliferation of memory CD8 T cells. J. Immunol. 2005. 174: 1269–1273. 45 Mamani-Matsuda, M., Cosma, A., Weller, S., Faili, A., Staib, C., Garcon, L., Hermine, O. et al., The human spleen is a major reservoir for long-lived vaccinia virus-specific memory B cells. Blood 2008. 111: 4653–4659. 46 Martinez-Gamboa, L., Mei, H., Loddenkemper, C., Ballmer, B., Hansen, A., Lipsky, P. E., Emmerich, F. et al., Role of the spleen in peripheral memory B-cell homeostasis in patients with autoimmune thrombocytopenia purpura. Clin. Immunol. 2009. 130: 199–212.

34 Harrington, L. E., Janowski, K. M., Oliver, J. R., Zajac, A. J. and Weaver, C. T., Memory CD4 T cells emerge from effector T-cell progenitors. Nature 2008. 452: 356–360. 35 Stemberger, C., Huster, K. M., Koffler, M., Anderl, F., Schiemann, M., Wagner, H. and Busch, D. H., A single naive CD81 T cell precursor can develop into diverse effector and memory subsets. Immunity 2007. 27: 985–997.

Full correspondence: Professor Andreas Radbruch, Deutsches Rheumaforschungszentrum Berlin, Wissenschaftsgemeinschaft Leibniz, Germany Fax: 149-30-28-460-603 e-mail: [email protected]

36 Sallusto, F., Lenig, D., Forster, R., Lipp, M. and Lanzavecchia, A., Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature 1999. 401: 708–712. 37 Breitfeld, D., Ohl, L., Kremmer, E., Ellwart, J., Sallusto, F., Lipp, M. and Forster, R., Follicular B helper T cells express CXC chemokine receptor 5, localize to B cell follicles, and support immunoglobulin production. J. Exp. Med. 2000. 192: 1545–1552.


See accompanying articles: All articles in this issue’s memory review series Received: 21/4/2009 Revised: 15/6/2009 Accepted: 15/6/2009

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