Bone Marrow Is a Major Reservoir and Site of Recruitment for Central Memory CD8+ T Cells

Mazo, Irina B.; Honczarenko, Marek; Leung, Howan; Cavanagh, Lois L.; Bonasio, Roberto; Weninger, Wolfgang; Engelke, Katharina; Xia, Lijun; McEver, Rodger P.; Koni, Pandelakis A.; Silberstein, Leslie E.; Andrian, Ulrich H. von

doi:10.1016/j.immuni.2005.01.008

Cited by 322 publications

(382 citation statements)

References 70 publications

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“…Our finding is in accordance with a recent study showing preferential homing and retention of murine T CM in BM following adoptive transfer [22]. In previous studies we found melanoma-specific T CM in BM but not in PB in patients immunized with a peptide vaccine [23,24].…”

Section: Discussionsupporting

confidence: 93%

CMV‐specific central memory T cells reside in bone marrow

Letsch

Knödler

et al. 2007

Eur J Immunol

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CMV-specific CD8 + T cell responses in peripheral blood (PB) are characterized by a preponderance of effector and effector memory T cells. CMV-specific central memory T cells (T CM ), which are considered crucial in maintaining long-term immunity, are rarely detectable in PB. In this study we have analyzed differentiation and function of CMV pp65-specific CD8 + T cells in paired samples of human PB and BM using intracellular cytokine and tetramer staining. Overall frequencies of CMV pp65-specific T cells were similar in PB compared to BM; however, CMV-specific CD45RA -CCR7 + T CM were almost exclusively detectable in BM, which was not related to a general accumulation of T CM in BM. In vitro, CMV-specific T cells could be more efficiently expanded from BM (median 128-fold, n=6) than from PB (median 72-fold, p=0.01). Taken together, these data show that the BM is a compartment harboring CMV-specific T CM and underline the concept of the BM as a secondary immune organ. CMV specific BM-derived T CM might be a valuable source for generating T cells for adoptive transfer. IntroductionBased on phenotypic and functional characteristics two main populations of memory T cells can be distinguished: central memory T cells (T CM ), expressing the chemokine receptor CCR7, and effector memory T cells (T EM ), lacking lymph node homing receptors and migrating to peripheral tissues [1]. Both subsets can differentiate into effector T cells (T Eff ). The generally accepted concept holds that T CM have a higher proliferative potential and a greater capacity than T EM for long-lasting persistence in vivo [2][3][4].There is growing evidence suggesting that CD8 + T CM play a key role in long-term protection against acute infections in vivo [5][6][7]. In the chronic phase of persistent infections, differences in T cell differentiation were found dependent on viral specificity [8]. In general, specific CD8 + T cell responses against CMV and other chronic viral infections found in peripheral blood (PB) were CCR7 -belonging to T EM and T EFF [8][9][10][11]. It is unclear yet, whether the failure to detect CMV-specific CCR7 + T CM is related to the specific situation of chronic infection, where continuous stimulation of T cells occurs, or is due to their retention in lymphoid tissues. Information concerning the anatomical distribution of T cell differentiation subsets of virusspecific T cells in humans is very limited. In the study by Ellefsen et al.[10], however, several fold lower * These two authors contributed equally to this work. frequencies of CMV pp65-specific tetramer + CD8 + T cells were found in lymph nodes compared to PB. Recently the BM was identified as an important site for accumulation and proliferation of memory T cells [12][13][14]. Furthermore, there is growing evidence of the BM as secondary lymphoid organ priming naive T cells (T N ) and also efficiently stimulating memory T cells [15,16].In this study we comparatively analyzed the differentiation subsets of CMV pp65-specific CD8 + T cells in human PB and BM samples o...

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Section: Discussionsupporting

confidence: 93%

CMV‐specific central memory T cells reside in bone marrow

Letsch

Knödler

et al. 2007

Eur J Immunol

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“…Thus, T cells exert a negative effect on the NK cell compartment. As mentioned above memory CD8 T cells [5,24], which are prominently present also in BM [41], TCRab NKT cells [25] and TCRcd cells [26] all depend on IL-15 for their peripheral survival. Indeed, it has been shown that NK cells compete with NKT cells [25] or with TCRcd cells [26] for the available IL-15.…”

Section: Nk Cells In T Cell-deficient Micementioning

confidence: 77%

T and B lymphocytes exert distinct effects on the homeostasis of NK cells

2006

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There is growing evidence that lymphocytes impact the development and/or function of other lymphocyte populations. Based on such observations we have tested whether the NK cell compartment was phenotypically and functionally altered in the absence of B and/or T cells. Here we show that T cell deficiency significantly accelerates BM NK cell production and the subsequent seeding of splenic and liver NK cell compartments. In contrast, B cell deficiency reduces splenic NK cell survival. In the absence of T and B cells, the size of the NK cell compartments is determined by the combination of these positive and negative effects. Even though NK cell homeostasis is significantly altered, NK cells from T and/or B cell-deficient mice show a normal capacity to kill a susceptible target cell line and to produce IFN. Nevertheless, we noted that the usage of MHC class Ispecific Ly49 family receptors was significantly altered in the absence of T and/or B cells. In general, B cell deficiency expanded Ly49 receptor usage, while T cell deficiency exerted both positive and negative effects. These findings show that B and T cells significantly and differentially influence the homeostasis and the phenotype of NK cells.

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“…We decided to use parietal bone in which the distance from the bone surface to the bone marrow cavity is 80-120 μm (within the appropriate range for two-photon microscopy). We modified the method used in a pilot study, which revealed that central memory CD8 + T cells were preferentially recruited to, and accumulated in, the bone marrow cavity and interacted with mature circulating dendritic cells Mazo et al, 2005).…”

Section: Application Of Intravital Imaging To the Analysis Of Cell Bementioning

confidence: 99%

The Role of Sphingosine 1-Phosphate in Migration of Osteoclast Precursors; an Application of Intravital Two-Photon Microscopy

Ishii

Shimazu

Nishiyama

et al. 2011

Molecules and Cells

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Sphingosine-1-phosphate (S1P), a biologically active lysophospholipid that is enriched in blood, controls the trafficking of osteoclast precursors between the circulation and bone marrow cavities via G protein-coupled receptors, S1PRs. While S1PR1 mediates chemoattraction toward S1P in bone marrow, where S1P concentration is low, S1PR2 mediates chemorepulsion in blood, where the S1P concentration is high. The regulation of precursor recruitment may represent a novel therapeutic strategy for controlling osteoclast-dependent bone remodeling. Through intravital multiphoton imaging of bone tissues, we reveal that the bidirectional function of S1P temporospatially regulates the migration of osteoclast precursors within intact bone tissues. Imaging technologies have enabled in situ visualization of the behaviors of several players in intact tissues. In addition, intravital microscopy has the potential to be more widely applied to functional analysis and intervention.

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Bone Marrow Is a Major Reservoir and Site of Recruitment for Central Memory CD8+ T Cells

Cited by 322 publications

References 70 publications

CMV‐specific central memory T cells reside in bone marrow

CMV‐specific central memory T cells reside in bone marrow

T and B lymphocytes exert distinct effects on the homeostasis of NK cells

The Role of Sphingosine 1-Phosphate in Migration of Osteoclast Precursors; an Application of Intravital Two-Photon Microscopy

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