Human Bone Marrow: A Reservoir for “Enhanced Effector Memory” CD8+ T Cells with Potent Recall Function

Zhang, Xiaoyu; Dong, Haidong; Lin, Wei; Voss, Stephen G.; Hinkley, Lucinda; Westergren, Melissa; Tian, Guo‐Liang; Berry, Daniel J.; Lewellen, D. C.; Vile, Richard G.; Chen, Lieping; Farber, Donna L.; Strome, Scott E.

doi:10.4049/jimmunol.177.10.6730

Cited by 45 publications

(59 citation statements)

References 56 publications

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“…We observed similar frequencies of CMV-specific T cells in PB and BM in accordance with a recent study by Zhang et al [17]. Consistent with previous reports we found that the majority of CD8 + CMV-specific T cells in PB were of T Eff and T EM phenotype [10,18,19], while we could demonstrate here that a large pool of CMV-specific T CM is present in BM.…”

Section: Introductionsupporting

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: Introductionsupporting

confidence: 93%

CMV‐specific central memory T cells reside in bone marrow

Letsch

Knödler

et al. 2007

Eur J Immunol

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“…Therefore, vaccinated animals inoculated with IL-15 or IL-7 cytokine, at the time of minimal to absent response (W18-W26), should experience earlier re-emergence of HIV-specific CD8 ϩ T cells. 2) Subsets of HIV-specific memory CD8 ϩ T cells with strong recall function may early reside in particular anatomic compartment (e.g., bone marrow) as reported recently (33). After an extensive absence of Ag and possibly unknown signals, these cells may progressively relocate in secondary lymphoid tissues like the spleen.…”

Section: Discussionmentioning

confidence: 88%

Phenotypic and Functional Analysis of Immune CD8+ T Cell Responses Induced by a Single Injection of a HIV DNA Vaccine in Mice

Arrode

Hegde

Mani

et al. 2007

The Journal of Immunology

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HIV DNA vaccines are potent inducers of cell-mediated immune (CMI) response in mice but elicit poor HIV-specific IFN-γ-producing T cells in monkeys and humans. In this study, we performed kinetic analyses on splenocytes of BALB/c mice that were immunized by a single injection with a unique DNA vaccine. Using IFN-γ-ELISPOT and multiparametric FACS analysis, we characterized the induced CMI response. We found that the response was detectable for at least 63 wk. ELISPOT detection of IFN-γ-producing T cells showed a profile with two waves separated by a long period of minimal response. Multiparametric FACS analysis showed two populations of CD3+CD8+ T cells that were specific for all HIV Ags. These cells had similar robust proliferation abilities and contained granzyme B. However, only a few produced IFN-γ. Both IFN-γ-producing and non-IFN-γ-producing HIV-specific CD8+ T cells were detected in the early stage (week (W)1 and W2 postimmunization (PI)), in the prolonged intermediate period of minimal response (W4-W26 PI), and in the final late phase of increased response (W30-W63 PI). Our longitudinal characterization showed that both subsets of cells underwent expansion, contraction, and memory generation/maintenance phases throughout the lifespan of the animal. Altogether, these findings bring insight to the heterogeneity of the immune T cell response induced by a single immunization with this DNA and strengthen the concept that used of the IFN-γ-ELISPOT assay alone may be insufficient to detect critical T cell responses to candidate HIV vaccines.

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“…In this respect, melanoma antigen-specific memory T cells are of special interest because they are known to react to antigens (including tumor antigens) faster and stronger than naive T cells by increased proliferation; they release a broader spectrum of cytokines and need less costimulation by professional antigen presenting cells (4)(5)(6). Our previous studies in breast cancer patients (7)(8)(9) as well as publications of other authors (10)(11)(12) provided strong evidence that the bone marrow (BM) is a major site for persistence of tumor-specific memory T cells with central memory (CM) and effector memory (EM) phenotype. Furthermore, the BM has been recently described as a central organ in memory T-cell migration (13).…”

Section: Introductionmentioning

confidence: 93%

Melanoma-Specific Memory T Cells Are Functionally Active inRetTransgenic Mice without Macroscopic Tumors

et al. 2008

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We previously reported that bone marrows of breast cancer patients contained tumor antigen-specific CD8 + T cells with central or effector memory phenotype. Using a recently developed ret transgenic mouse melanoma model, we now show that bone marrows and tumors of transgenic mice contain high frequencies of CD8 + T cells specific for the melanoma antigen tyrosinase-related protein 2 and showing mostly effector memory phenotype. Moreover, increased numbers of bone marrow tyrosinase-related protein-2-specific effector memory CD8 + T cells are also detected in transgenic animals older than 20 weeks with disseminated melanoma cells in the bone marrow and lymph nodes but showing no visible skin tumors and no further melanoma progression. After a short-term coincubation with dendritic cells generated from the bone marrow and pulsed with melanoma lysates, bone marrow memory T cells from mice without macroscopic melanomas produced IFN-; in vitro and exerted antitumor activity in vivo after adoptive transfer into melanoma-bearing mice. Our data indicate that functionally active bone marrowderived melanoma-specific memory T cells are detectable at the phase of microscopic tumor load, suggesting that thereby they could control disseminated melanoma cells. [Cancer Res 2008;68(22):9451-8]

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Human Bone Marrow: A Reservoir for “Enhanced Effector Memory” CD8+ T Cells with Potent Recall Function

Cited by 45 publications

References 56 publications

CMV‐specific central memory T cells reside in bone marrow

CMV‐specific central memory T cells reside in bone marrow

Phenotypic and Functional Analysis of Immune CD8+ T Cell Responses Induced by a Single Injection of a HIV DNA Vaccine in Mice

Melanoma-Specific Memory T Cells Are Functionally Active inRetTransgenic Mice without Macroscopic Tumors

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