Expansion of CD56-Negative, CD16-Positive, KIR-Expressing Natural Killer Cells after T Cell-Depleted Haploidentical Hematopoietic Stem Cell Transplantation

Division of Hematology and Clinical Immunology, Department of Clinical and Experimental Medicine, University of Perugia, Perugia, Italy.
Acta Haematologica (Impact Factor: 1.12). 03/2011; 126(1):13-20. DOI: 10.1159/000323661
Source: PubMed


The main functions of natural killer (NK) cells are early protection against viruses or tumor cells and production of cytokines that regulate immune functions. The present study assessed the role of different NK subsets in exerting graft-versus-leukemia effects in recipients of human leukocyte antigen (HLA) haploidentical hematopoietic transplants and monitored for the first time CD3-/CD56- lymphocyte expansion. CD3-/CD56- cells expressed NK cell-associated molecules, such as CD16, NKp46, NKp30, CD244 (2B4), CD161, and killer cell immunoglobulin-like receptors. CD3-/CD56- cells further exhibited the classical functional characteristics of NK cells: cytolysis of target cells lacking HLA class I, antibody-dependent cellular cytotoxicity and cytokine production. These results demonstrate that CD56- NK cells are functional, recognize missing self and, like their CD56+ counterparts, may contribute to graft-versus-leukemia reactions.

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    • "In addition, a third subset, characterized by a CD56−CD16+ surface phenotype, exists, but is rare in healthy individuals and represents a small percentage of total NK cells. However, expansion of CD56− NK cells have been described in HIV and HCV chronically infected subjects (16, 17) and also in recipients of hematopoietic stem cell transplantation (HSCT) (18, 19). "
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    ABSTRACT: Natural Killer (NK) cell function is regulated by an array of inhibitory and activating surface receptors that during NK cell differentiation, at variance with T and B cells, do not require genetic rearrangement. Importantly, NK cells are the first lymphocyte population recovering after hematopoietic stem cell transplantation (HSCT). Thus, their role in early immunity after HSCT is considered crucial, as they can importantly contribute to protect the host from tumor recurrence and viral infections before T-cell immunity is fully recovered. In order to acquire effector functions and regulatory receptors, NK cell precursors undergo a maturation process that can be analyzed during immune reconstitution after HSCT. In this context, the occurrence of human cytomegalovirus (HCMV) infection/reactivation was shown to accelerate NK cell maturation by promoting the differentiation of high frequencies of NK cells characterized by a KIR(+)NKG2A(-) and NKG2C(+) mature phenotype. Thus, it appears that the development of NK cells and the distribution of NK cell receptors can be deeply influenced by HCMV infection. Moreover, in HCMV-infected subjects the emergence of so called "memory-like" or "long-lived" NK cells has been documented. These cells could play an important role in protecting from infections and maybe from relapse in patients transplanted for leukemia. All the aspects regarding the influence of HCMV infection on NK cell development will be discussed.
    Full-text · Article · Dec 2013 · Frontiers in Immunology
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    • "It is unclear whether CD56neg cells identified in cord blood and in other settings represent a common population, or to what extent they might acquire distinct characteristics over the course of chronic viral infection [19], [23], [37] or following hematopoietic transplantation [24], [25]. Of interest, the CD56neg cells described in this study, whether from healthy adult blood, cord blood or HIV-infected blood, showed similar patterns of activating/inhibitory receptors, suggesting that this subset may represent an immature population of NK cells rather than a dysfunctional subset, even in HIV-infected individuals. "
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    ABSTRACT: Neonatal Natural Killer (NK) cells show functional impairment and expansion of a CD56 negative population of uncertain significance. NK cells were isolated from cord blood and from adult donors. NK subpopulations were identified as positive or negative for the expression of CD56 and characterized for expression of granzyme B and surface markers by multi-parameter flow cytometry. Cell function was assessed by viral suppression and cytokine production using autologous lymphocytes infected with HIV. Activating (NKp30, NKp46) and inhibitory (Siglec-7) markers in healthy infants and adults were compared with viremic HIV-infected adults. Cord blood contained increased frequencies of CD56 negative (CD56neg) NK cells with reduced expression of granzyme B and reduced production of IFNγ and the CC-class chemokines RANTES, MIP1α and MIP1β upon stimulation. Both CD56pos and CD56neg NK subpopulations showed impaired viral suppression in cord blood, with impairment most marked in the CD56neg subset. CD56neg NK cells from cord blood and HIV-infected adults shared decreased inhibitory and activating receptor expression when compared with CD56pos cells. CD56neg NK cells are increased in number in normal infants and these effectors show reduced anti-viral activity. Like the expanded CD56neg population described in HIV-infected adults, these NK cells demonstrate functional impairments which may reflect inadequate development or activation.
    Full-text · Article · Jun 2013 · PLoS ONE
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    ABSTRACT: Natural killer (NK) cells play a crucial role in early immunity after hematopoietic stem cell transplantation because they are the first lymphocyte subset recovering after the allograft. In this study, we analyzed the development of NK cells after intrabone umbilical cord blood (CB) transplantation in 18 adult patients with hematologic malignancies. Our data indicate that, also in this transplantation setting, NK cells are the first lymphoid population detectable in peripheral blood. However, different patterns of NK-cell development could be identified. Indeed, in a group of patients, a relevant fraction of NK cells expressed a mature phenotype characterized by the KIR(+)NKG2A(-) signature 3-6 months after transplantation. In other patients, most NK cells maintained an immature phenotype even after 12 months. A possible role for cytomegalovirus in the promotion of NK-cell development was suggested by the observation that a more rapid NK-cell maturation together with expansion of NKG2C(+) NK cells was confined to patients experiencing cytomegalovirus reactivation. In a fraction of these patients, an aberrant and hyporesponsive CD56(-)CD16(+)p75/AIRM1(-) NK-cell subset (mostly KIR(+)NKG2A(-)) reminiscent of that described in patients with viremic HIV was detected. Our data support the concept that cytomegalovirus infection may drive NK-cell development after umbilical CB transplantation.
    Full-text · Article · Nov 2011 · Blood
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