Forum in Immunology

Introduction: regulation of lymphocyte homeostasis

The present Forum deals with homeostasis of lympho-cyte numbers. In an adult mammal the number of lympho-cytes is regulated and shows “a return tendency, due to adensity-dependent process, to approach a stationary distri-bution of population densities”, i.e. homeostasis[1]. Aslymphocytes are continuously generated in the centrallymphoid organs and removed from the peripheral compart-ments, the stationary distribution is a steady state oflymphocyte generation, survival, differentiation, and apop-tosis. Introduction of a perturbation may decrease (a cyto-static treatment) or increase (an antigenic stimulation) totallymphocyte numbers, but once the perturbation is removed,lymphocyte numbers return to the previous equilibriumlevel.

Accordingly, a mouse with an ‘abnormal’ number of Band T cells does not necessarily have perturbed homeosta-sis. In fact, few conditions can be referred to as bona fideexamples of defective homeostasis. IL-2Rα-deficient micedo have disturbed homeostasis, since in these mice thenumber of lymphoid cells increases in an uncontrolledfashion until death occurs[2]. Lymphoid tumors are classi-cal examples of cells escaping homeostatic control. The factthat a mouse transplanted with 10–20 ectopic thymuses mayhave a slight increase in the number of peripheral T cellsdoes not mean that its homeostasis is loose, but that in theresulting mouse, the homeostatic equilibrium is set at ahigher level due to increased levels of T-cell generation[3].Once the transplants are removed, the number of T cellsreturns to the normal level. A thymectomized mouse repre-sents the opposite situation where a homeostatic number ofperipheral T cells is kept stable at a new, lower level.Similarly, an HIV-infected individual does not have per-turbed homeostasis. As HIV infection results in a more rapidremoval of existing T cells, the homeostatic equilibrium isset at a much lower level. Once the infectious insult isreduced, the numbers of lymphocytes tend to increase to thenormal level, demonstrating that homeostatic regulationsare preserved[4,5]. In most patients, however, the numberof lymphocytes never really gets back to the normal level.The HIV infection may induce irreversible changes in thehost that lead to the establishment of new homeostaticequilibrium that is different from that of a healthy indi-vidual. In addition, an RAG-deficient mouse[6] does nothave dysfunctional homeostasis. It just happens that in the

RAG-deficient mouse, which cannot produce any B or Tcells, the homeostatic control of lymphocyte numbers is setat zero. If a population of T cells is introduced into theRAG-deficient host, these T cells expand and reach steady-state numbers. In this new mouse (RAG host reconstitutedwith T cells), the homeostatic equilibrium differs from thatof an intact mouse and varies according to the transferredcell population[7]. Therefore, lymphocyte homeostasis is adynamic process and operates at different levels for differentsystems.

By comparing the homeostatic levels of different systemswe hope to understand two related, but different questions:(i) What determines the number of peripheral lymphocytes?(ii) Which mechanisms contribute to the maintenance ofsteady-state cell numbers? Various studies have shown thathomeostasis of T- and B-cell numbers is regulated indepen-dently. For T cells, evidence also suggests that the homeo-stasis of naïve and memory T-cell compartments is regu-lated independently. The number of naïve T cells istherefore determined by the rate of new T-cell generationand emigration from the thymus, and survival, proliferation,and exit of existing naïve cells from the compartment (e.g.becoming effector or memory cells or undergoing apopto-sis). Similarly, the generation, survival, proliferation, andexit of memory T cells determine the size of the memoryT-cell compartment. The total number of T cells is thesumming up of naïve and memory T cells.

Several lines of evidence show that the total number ofperipheral lymphocytes is not determined by rate of produc-tion of new cells in the central lymphoid organs but isregulated in the periphery. The correlation between the ratesof B-cell production in the bone marrow (BM) and the sizeof the peripheral B-cell pools was studied in mouse chime-ras containing different numbers of competent precursorpre-B cells [8]. Lethally irradiated B-cell-deficient micewere reconstituted with normal BM cells alone or BM cellsfrom normal and B-cell-deficient mice mixed at severalratios. In the resulting chimeras, and since normal precursorcells are diluted among incompetent precursors, the numberof pre-B cells was reduced according to the fraction ofnormal competent cells present in the initial BM inoculum.Comparing the total number of B cells in these differentmouse chimeras, it was found that mice containing only30% of the normal number of pre-B cells fully reconstituted

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the peripheral B-cell pools [8]. These results demonstratethat about 1/3 of the normal number of the BM B-cellprecursors suffices to maintain the peripheral B-cell poolsize of a BM irradiation chimera. The same question wasaddressed by a complementary approach. Parabiosis be-tween one normal mouse and two B-cell-deficient miceresulted in a triad of mice with the number of pre-B cells ofa single control mouse and approximately threefold moreperipheral B cells [8]. These experiments directly demon-strate that the physiological BM B-cell production of onemouse is sufficient to replenish the peripheral B-cell poolsof two to three mice and suggest that the number ofperipheral B cells is limited by yet unknown peripheralmechanisms.

Similarly, the total numbers of peripheral T cells are notdetermined by the rate of production of T cells in the thymusbut are regulated in the periphery. Thymectomy in neonataland adult mice results in a permanently reduced size of theperipheral T-cell pool. In both cases, however, a significantnumber of T cells persist in the absence of the thymus [9].Engraftment of multiple thymus lobes increases the func-tional thymus mass and the number of recent thymusemigrants. The peripheral T-cell pool size, however, doesnot increase proportionally to the overall increase in thymusmass [3]. By assessing the fraction of competent precursorsrequired to repopulate the thymus and quantify the relation-ship between the size of the different T-cell compartmentsduring T-cell maturation in the thymus, Almeida et al. [10]showed that the sizes of the peripheral CD4 and CD8 T-cellpools are largely independent of the number of precursorsand of the number of thymus cells.

What are the mechanisms that regulate steady-statelymphocyte numbers in the periphery after they are gener-ated? This question is the focus of discussion of the presentedition of the Forum. Specific topics include the require-ment of self-peptide/MHC complexes and cytokines in bothnaïve and memory T-cell survival and homeostasis-drivingproliferation, contributions of thymopoiesis andhomeostasis-driven proliferation to the reconstitution of thenaïve and memory compartments, the role of regulatory Tcells, and the reconstitution of T cells in HIV patients after

antiviral therapy. Although many issues are still controver-sial, it is the hope of this Forum that hard facts aredistinguished from hypotheses and that both sides of thearguments are presented.

References

[1] I. Hanski, Metapopulation Ecology, Oxford University Press, Ox-ford, 1999.

[2] D.M. Willerford, J. Chen, J.A. Ferry, L. Davidson, A. Ma, F.W. Alt,Interleukin-2 receptor alpha chain regulates the size and content ofthe peripheral lymphoid compartment, Immunity 3 (1995) 521–530.

[3] S.P. Berzins, R.L. Boyd, J.F. Miller, The role of the thymus andrecent thymic migrants in the maintenance of the adult peripherallymphocyte pool, J. Exp. Med. 187 (1998) 1839–1848.

[4] B. Autran, G. Carcelain, T.S. Li, C. Blanc, D. Mathez, R. Tubiana,C. Katlama, P. Debre, J. Leibowitch, Positive effects of combinedantiretroviral therapy on CD4+ T cell homeostasis and function inadvanced HIV disease, Science 277 (1997) 112–116.

[5] C.L. Mackall, F.T. Hakim, R.E. Gress, Restoration of T-cell homeo-stasis after T-cell depletion, Seminars Immunol. 9 (1997) 339–346.

[6] Y. Shinkai, G. Rathbun, K.P. Lam, E.M. Oltz, V. Stewart, M. Men-densohn, J. Charron, M. Datta, F. Young, A.M. Stall, F.W. Alt,RAG-2-deficient mice lack mature lymphocytes owing to inabilityto initiate V(D)J rearrangement, Cell 68 (1992) 855–867.

[7] A.A. Freitas, B. Rocha, Lymphocyte population biology: the flightfor survival, Annu. Rev. Immunol. 18 (2000) 83–111.

[8] F. Agenes, M.M. Rosado, A.A. Freitas, Independent homeostaticregulation of B cell compartments, Eur. J. Immunol. 27 (1997)1801–1807.

[9] J.F. Miller, Effect of thymectomy in adult mice on immunologicalresponsiveness, Nature 208 (1965) 1337–1338.

[10] A.R.M. Almeida, J.A.M. Borghans, A.A. Freitas, T cell homeostasis:thymus regeneration and peripheral T cell restoration in mice with areduced fraction of competent precursors, J. Exp. Med. 194 (2001)591–599.

Antonio Freitas a, Jianzhu Chen b,*aBiologie des populations lymphocytaires, CNRS 1961,

departement d’immunologie, Institut Pasteur,25, rue du Dr. Roux, 75724 Paris, France

bCenter for Cancer Research and Department of Biology,Massachusetts Institute of Technology, Cambridge,

MA 02139, USAE-mail address: jchen@mit.edu (J. Chen).

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