Immunity, Vol. 22, 143–144, February, 2005, Copyright ©2005 by Elsevier Inc. DOI 10.1016/j.immuni.2005.02.002

Preview

Immunity: It’s in Our Bones

Accumulating data suggest that the bone marrow isa reservoir for memory CD8+ T cells. In this issue ofImmunity, Mazo et al. (2005) show that bone marrowCD8+ T cells are predominantly CCR7+/CD62L+

“central memory” cells and describe specific signalsthat mediate their constitutive recruitment from theblood.

In the past, immunologists have tended to have a rathercentrist view of the immune system. T and B cells de-veloped in the thymus and bone marrow, respectively,and the lymph nodes and spleen were considered tobe the central reservoirs of adaptive immunity and weretherefore the focus of intense scrutiny. Over time, how-ever, it has become increasingly apparent that the im-mune system has a far more decentralized governingsystem. First came the realization that lymphoid tissuesat mucosal sites had their own specific organizationuniquely adapted to mediate specialized functions. Se-cond was the observation that lymphoid tissues can begenerated de novo at nonlymphoid sites in response tolocal infections. Finally, the bone marrow was shown toplay several unexpected roles, including serving as animportant reservoir for memory T cell populations.

The bone marrow has long been known to play acentral role in the immune system as a primary hemato-poietic organ. However, there has been a growing real-ization that the bone marrow may also play a moreintegral role in immune responses by hosting and regu-lating adaptive immunity. A key advance was the dis-covery that the bone marrow is a reservoir for long-lived, antibody-secreting plasma cells and is thusinvolved in the maintenance of long immunity (Slifka etal., 1998). With respect to T cells, it has been shownthat under certain conditions, the bone marrow canserve as a site for the initiation of naive T cell responses(Feuerer et al., 2003; Tripp et al., 1997). Furthermore, anumber of reports have also indicated that bone mar-row might be a reservoir for memory T cells, althoughit was not clear whether the cells were just circulatingthrough the marrow or whether there were specificmechanisms of recruitment (Di Rosa and Santoni, 2003;Klonowski et al., 2004).

Now, an elegant study in this issue of Immunity(Mazo et al., 2005) demonstrates that central memoryCD8+ T cells are preferentially recruited to, and accu-mulate in, the bone marrow. This recruitment is amultistep process involving PSGL-1- (and indirectlyCD62L-) mediated rolling and VLA-4-mediated arrest inbone marrow venules. Surprisingly, the arrest of cellsalso appears to be enhanced by CXCL12 (a ligand forCXCR4 on central memory T cells) yet does not abso-lutely require G proteins, which is uncharacteristic of

chemokine signaling. However, G protein-coupled re-ceptors were involved in the subsequent emigration ofthe cells into bone marrow cavities. These data begin toprovide a mechanistic explanation for the preferentialaccumulation of central memory T cells in the bonemarrow. The involvement of CD62L explains the prefer-ential accumulation of central memory cells (as op-posed to CD62L− effector memory cells). In addition, apostulated requirement for high levels of CD62L oncentral memory T cells in this process further distin-guishes their recruitment from that of circulatinghematopoietic stem cells, which are recruited in aCD62L-independent manner, even though they expressmoderate levels of CD62L.

An interesting feature of these findings is the rela-tively large number of central memory cells that accu-mulate in bone marrow in both the mouse model andhuman. It is possible that the bone marrow simply con-stitutes a useful storage site for these cells. The evolu-tionary drive to lighten the weight of bones by makingthem hollow has provided an excellent niche for othercells and systems. (This is not dissimilar from the aer-oengineering trick of using the hollow wings of aircraftto carry fuel.) However, it is also possible that the bonemarrow is a prime source of factors required for themaintenance of central memory T cells. In this regard,it has recently been shown that the bone marrow is apreferred site for the IL-15-dependent homeostatic pro-liferation of memory T cells (Becker et al., 2005). Aninteresting possibility is that the high numbers ofcentral memory T cells in the bone marrow and theirincreased rate of homeostatic proliferation may be amajor mechanism in the progressive accumulation ofcentral memory T cells over time in the secondary lym-phoid organs (Wherry et al., 2003). In addition, it hasbeen shown that entry into the bone marrow is compet-itive and saturable (Di Rosa and Santoni, 2003). Thisraises the possibility that the bone marrow in aged micebecomes progressively filled with functionally defectivememory CD8+ T cells that arise as a consequence ofclonal expansions in aged individuals. Indeed, thesecells accumulate within the bone marrow in murinemodels of osteoporosis and have also been shown tocorrelate with increased frequencies of osteoporoticfractures in the elderly (Effros, 2004). These observa-tions are consistent with emerging evidence that T cellsin the bone marrow may be directly involved in regulat-ing bone resorption and bone formation. This may be aclassic example of biological economy—the linking ofimmunity with other basic physiological functions.

Although it is now clear that central memory cells areselectively recruited to the bone marrow, many ques-tions remain. There are still details to be worked outregarding the recruitment process. For example, therole of CXCL12, which is abundantly produced by bonemarrow stromal cells, remains unclear, especially inlight of the fact that it has two distinct isoforms. In addi-tion, the role of LFA-1 is unresolved. Although excludedin the current study as a major player in memory cell

Immunity144

recruitment to the bone marrow, another study argued DTthat either LFA-1 or the α4 integrins play a key role in

lymphocyte recirculation through bone marrow (Berlin- 1SRufenach et al., 1999). Mazo et al. (2005) conclude that

there are likely to be additional rolling pathways in-volved, as inhibition of all selectins did not abolish roll-

Sing, and additional unidentified adhesion receptors maybe involved in bone marrow sticking. There are also

Bquestions regarding the role of the bone marrow in re- Icall responses. Although the bone marrow can appa- Brently function as a primary site of T cell expansion un- Mder particular conditions (Feuerer et al., 2003; Tripp et 1al., 1997), the specific contribution of bone marrow Dmemory T cells in recall responses remains to be deter- Emined. Consistent with their central memory pheno- Ftype, Mazo et al. (2005) show that the resident bone m

amarrow memory cells have the capacity to produce ef-Kfector cytokines when triggered by specific antigen. AEkey question is where do these cells encounter anti-Mgen? Is the resident population of bone marrow mem-Rory T cells static, waiting for antigen to be presented(

by resident or migrating DC, or does the bone marrowS

serve as home base for a population of roving “senti- nnel” memory T cells? It is possible that both mech-

Tanisms operate and that they may be mediated by Idistinct subsets of central memory cells. Trafficking Wstudies and further subset analysis will be required to S

maddress these questions.

avid L. Woodland and Marcia A. Blackmanrudeau Institute, Inc.54 Algonquin Avenuearanac Lake, New York 12983

elected Reading

ecker, T.C., Coley, S.M., Wherry, E.J., and Ahmed, R. (2005). J.mmunol. 174, 1269–1273.

erlin-Rufenach, C., Otto, F., Mathies, M., Westermann, J., Owen,.J., Hamann, A., and Hogg, N. (1999). J. Exp. Med. 189, 1467–

478.

i Rosa, F., and Santoni, A. (2003). Immunology 108, 296–304.

ffros, R.B. (2004). Exp. Gerontol. 39, 517–524.

euerer, M., Beckhove, P., Garbi, N., Mahnke, Y., Limmer, A., Hom-el, M., Hammerling, G.J., Kyewski, B., Hamann, A., Umansky, V.,

nd Schirrmacher, V. (2003). Nat. Med. 9, 1151–1157.

lonowski, K.D., Williams, K.J., Marzo, A.L., Blair, D.A., Lingenheld,.G., and Lefrancois, L. (2004). Immunity 20, 551–562.

azo, I.B., Honczarenko, M., Leung, H., Cavanagh, L.L., Bonasio,., Weninger, W., Engelke, K., Xia, L., McEver, R.P., Koni, P.A., et al.

2005). Immunity 22, this issue, 259–270.

lifka, M.K., Antia, R., Whitmire, J.K., and Ahmed, R. (1998). Immu-ity 8, 363–372.

ripp, R.A., Topham, D.J., Watson, S.R., and Doherty, P.C. (1997). J.mmunol. 158, 3716–3720.

herry, E.J., Teichgraber, V., Becker, T.C., Masopust, D., Kaech,.M., Antia, R., Von Andrian, U.H., and Ahmed, R. (2003). Nat. Im-unol. 3, 225–234.