Linking Immunity and Hematopoiesis by Bone Marrow T Cell Activity

BrazilianHematopoiesis Journal control of Medical and boneand Biological marrow T Research cells (2005) 38: 1475-1486 1475 ISSN 0100-879X Review Linking immunity and hematopoiesis by bone marrow T cell activity J.P. Monteiro1,2 1Divisão de Medicina Experimental, Coordenação de Pesquisa, and A. Bonomo1,3 Instituto Nacional de Câncer, Rio de Janeiro, RJ, Brasil 2Programa de Formação em Pesquisa Médica, Faculdade de Medicina, 3Instituto de Microbiologia Prof. Paulo de Góes, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brasil Abstract Correspondence Two different levels of control for bone marrow hematopoiesis are Key words A. Bonomo believed to exist. On the one hand, normal blood cell distribution is • T cell Coordenação de Pesquisa believed to be maintained in healthy subjects by an “innate” hemato- • Hematopoiesis Instituto Nacional de Câncer poietic activity, i.e., a basal intrinsic bone marrow activity. On the • Innate immunity Rua André Cavalcanti, 37 other hand, an “adaptive” hematopoietic state develops in response to • Adaptive immunity 20231-050 Rio de Janeiro, RJ • stress-induced stimulation. This adaptive hematopoiesis targets spe- Bone marrow Brasil • Immunological memory E-mail: [email protected] cific lineage amplification depending on the nature of the stimuli. Unexpectedly, recent data have shown that what we call “normal Presented at SIMEC 2004 hematopoiesis” is a stress-induced state maintained by activated bone (International Symposium marrow CD4+ T cells. This T cell population includes a large number on Extracellular Matrix), of recently stimulated cells in normal mice whose priming requires the Angra dos Reis, RJ, Brazil, presence of the cognate antigens. In the absence of CD4+ T cells or September 27-30, 2004. their cognate antigens, hematopoiesis is maintained at low levels. In Publication supported by CNPq this review, we summarize current knowledge on T cell biology, + and FAF/INCA. which could explain how CD4 T cells can help hematopoiesis, how they are primed in mice that were not intentionally immunized, and what maintains them activated in the bone marrow. Received February 16, 2005 Accepted May 25, 2005 Introduction Hematopoiesis control, i.e., the signals be “endocrinally” regulated through cyto- that govern lineage commitment and he- kines produced outside the bone marrow. matopoietic stem cell maintenance in adult While bone marrow-derived stimuli have bone marrow, has been extensively studied been viewed as important to maintain basal in the last decades. A large part of this con- blood cell production, peripheral stimuli have trol depends on the bone marrow microenvi- been related to hematopoiesis amplification ronment, where a complex network includ- during stress situations such as infection, ing multiple cell types such as fibroblasts, inflammation, irradiation, or hypoxia. Thus, osteocytes, endothelial cells, and all bone modulation of hematopoiesis has been viewed marrow-derived cells regulates hematopoie- as a systemically controlled phenomenon (1- sis through cytokine secretion and cellular 4). interactions. In addition, hematopoiesis can We have recently revisited this concept Braz J Med Biol Res 38(10) 2005 1476 J.P. Monteiro and A. Bonomo by showing that blood cell counts in normal lationship between T cells and hematopoie- mice are not the result of basal “innate” sis was influenced by the description of fail- hematopoietic activity (5). On the contrary, ure of bone marrow transplantation (BMT) they reflect the antigenic stimulation of bone in humans receiving T cell-depleted graft marrow CD4+ T cell. In other words, “nor- (11,12). At that time, BMT was already seen mal hematopoiesis” is not an innate state, as an important component of the treatment but an adaptive state, maintained by antigen of hematologic malignancies. However, the stimulation. In view of these novel findings major problem regarding BMT is graft-ver- and considering the potential role of CD4+ T sus-host disease (GVHD) (13), a severe dis- cells as a source of hematopoietins, we pro- ease mediated by T cells with high mortality posed these cells to be key regulators of and morbidity rates. Therefore, dissociation what we currently understand as “normal” of T cell GVHD activity and bone marrow hematopoiesis (5). engraftment activity was essential for the Here, we review the data that indirectly advance in BMT therapy. In addition, it was relate T cell and hematopoiesis and discuss shown that T cells also contribute to elimi- the recent findings which redefine hemato- nating residual neoplastic cells in BMT re- poiesis as a T cell-dependent phenomenon. cipient, introducing a new variable in this We also summarize the current knowledge equation (12). on T cell biology to explain how T cells can Thus, it is not surprising that almost all help hematopoiesis, how they are primed in the literature on T cell/hematopoiesis in the untreated (not intentionally immunized) last 25 years has been devoted to the role of mice, and how they are maintained in an T cells in hematopoiesis restoration after activated-state in the bone marrow. BMT. In fact, using bone marrow-radiation chimeras, several investigators reported the T cells and hematopoiesis - the old requirement for T cells in the establishment history of hematopoiesis after BMT (14,15). Ildstad et al. (16) used mixed allogeneic chimeras The role of thymus-derived cells in he- (B10 + B10.D2 → B10) to show that selec- matopoiesis was first suggested 30 years tive depletion of T cells in the bone marrow ago. Using the neonatal thymectomy model, inoculum conditioned the pattern of hemato- several investigators described that 1-day poietic reconstitution: if B10 bone marrow thymectomized mice were anemic, showed cells were T cell-depleted, B10.D2-derived arrested erythroid maturation and reduction cells were the predominant hematopoietic in the number of spleen colony-forming units cells in reconstituted mice, and vice-versa. in the bone marrow and spleen (6,7). In These data showed that histocompatibility addition, intravenous injection of live thy- between hematopoietic and T cells is neces- mocytes accelerated hematopoiesis recon- sary for their cooperation despite previous stitution in sublethally irradiated mice (8). interpretations that an allogeneic effect was All of these studies claimed the occurrence necessary for engraftment. of cooperation between hematopoietic cells The specificity of the T cell population and T cells for the establishment of optimal that causes GVHD and the population that hematopoiesis in mice. Supporting these data, helps hematopoiesis is still an unsolved ques- production of interleukin-3 (IL-3) and granu- tion. Different T cell subpopulations have locyte-macrophage colony-stimulating fac- been reported to be able to promote alloge- tors (GM-CSF) by T cells was described in neic bone marrow engraftment without caus- the early 80’s (9,10). ing GVHD (12,17). More specifically, the The increasing interest regarding the re- role of bone marrow T cells in the pathogen- Braz J Med Biol Res 38(10) 2005 Hematopoiesis control and bone marrow T cells 1477 esis of GVHD seems to be very minor, if any irradiation, bone marrow engraftment after (17). Only recently have these T cells been BMT, and amplification of hematopoiesis studied. The total bone marrow T cell popu- during infection, as cited above. However, it lation comprises 2-3% of all bone marrow is not clear if T cells contribute to hemato- cells. About one third of them are CD3+CD4- poiesis in the absence of such stresses. In CD8- or αßTCR+NK1.1+ cells (18). The role other words, do T cells play any major role of these unusual T cells in the bone marrow, in the maintenance of normal hematopoie- specifically regarding hematopoiesis, has not sis? Can T cells contribute to normal he- been evaluated. The remaining two thirds matopoietic activity upon interaction with are conventional αßTCR+ T cells enriched syngeneic bone marrow cells? And if so, in activated and memory CD4+ and CD8+ what is the stimulus? T cells (5,17,19,20). The potential of these The closest replies to these questions cells as hematopoietin providers or their cy- were obtained in the experiments reported tokine profile and the stimuli promoting their by Lord and Schofield (8) and by Bonomo et activation have never been investigated. al. (27). The former showed that injection of Besides conventional T cells, an unusual syngeneic thymocytes accelerates bone mar- type of “T cells”, the “facilitating cells”, was row reconstitution after sublethal irradia- described in bone marrow by Ildstad’s group tion. The latter, using an in vitro model, (21). These cells comprise 0.4% of total showed that syngeneic T cells stimulate the bone marrow cells and are CD8+CD3+CD45 growth of hematopoietic progenitors. RB-Thy1+class IIinterm cells. Curiously, these With the above findings in mind, we “T cells” do not express any known form of devoted our efforts to the study of normal T cell antigen receptor (TCR). They are hematopoiesis in athymic nude mice since devoid of allospecific activity and can help these animals lack all conventional T cells hematopoiesis. Therefore, although func- (5). Our findings were surprising: nude mice tional data on the activity of these cells are have a severe reduction in the number of abundant (21-23), their existence remains granulocytes in peripheral blood, despite the extremely controversial. high frequency of granulo-monocytic pro- In addition to the BMT model, the role of genitors in the bone marrow. Nude mice T cells in hematopoiesis was also investi- reconstitution with fetal thymus or purified gated in infectious disease models (24-26). CD4+ T cells not only restores the normal It appears that hematopoiesis amplification, granulocyte counts in peripheral blood, but required to clear pathogens, is deficient in also reduces the frequency of progenitors in athymic mice. This is true for the diverse bone marrow. In contrast, purified CD8+ blood cell types, although it is more impor- T cells are completely inefficient in restor- tant within the granulocytic compartment.

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