Warren D Shlomchik

Yale-New Haven Hospital, New Haven, Connecticut, United States

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Publications (54)443.3 Total impact

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    ABSTRACT: Regulatory T cells (Tregs), which express CD4 and FOXP3, are critical for modulating the immune response and promoting immune tolerance. Consequently, methods to expand Tregs for therapeutic use are of great interest. While transfer of Tregs after massive ex vivo expansion can be achieved, in vivo expansion of Tregs would be more practical. Here, we demonstrate that targeting the CD45 tyrosine phosphatase with a tolerogenic anti-CD45RB mAb acutely increases Treg numbers in WT mice, even in absence of exogenous antigen. Treg expansion occurred through substantial augmentation of homeostatic proliferation in the preexisting Treg population. Moreover, anti-CD45RB specifically increased Treg proliferation in response to cognate antigen. Compared with conventional T cells, Tregs differentially regulate their conjugation with DCs. Therefore, we determined whether CD45 ligation could alter interactions between Tregs and DCs. Live imaging showed that CD45 ligation specifically reduced Treg motility in an integrin-dependent manner, resulting in enhanced interactions between Tregs and DCs in vivo. Increased conjugate formation, in turn, augmented nuclear translocation of nuclear factor of activated T cells (NFAT) and Treg proliferation. Together, these results demonstrate that Treg peripheral homeostasis can be specifically modulated in vivo to promote Treg expansion and tolerance by increasing conjugation between Tregs and DCs.
    J Clin Invest. 09/2014; pii: 74087.
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    ABSTRACT: Maturation of T cell-activating APCs directly links innate and adaptive immunity and is typically triggered by microbial infection. Transplantation of allografts, which are sterile, generates strong T cell responses; however, it is unclear how grafts induce APC maturation in the absence of microbial-derived signals. A widely accepted hypothesis is that dying cells in the graft release "danger" molecules that induce APC maturation and initiate the adaptive alloimmune response. Here, we demonstrated that danger signals associated with dying cells are not sufficient to initiate alloimmunity, but that recognition of allogeneic non-self by the innate immune system is required. In WT as well as in T cell-, B cell-, and innate lymphoid cell-deficient mice, allogeneic grafts elicited persistent differentiation of monocytes into mature DCs that expressed IL-12 and stimulated T cell proliferation and IFN-γ production. In contrast, syngeneic grafts in the same mice elicited transient and less pronounced differentiation of monocytes into DCs, which neither expressed IL-12 nor stimulated IFN-γ production. In a model in which T cell recognition is restricted to a single foreign antigen on the graft, rejection occurred only if the allogeneic non-self signal was also sensed by the host's innate immune system. These findings underscore the importance of innate recognition of allogeneic non-self by monocytes in initiating graft rejection.
    The Journal of clinical investigation. 07/2014;
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    ABSTRACT: Graft-versus-host disease (GVHD) is a frequent major complication of allogeneic hematopoietic cell transplantation (HCT). The development of approaches that selectively deplete T cells that cause GVHD from allogeneic stem cell grafts and preserve T cells specific for pathogens may improve HCT outcomes. It has been hypothesized that the majority of T cells that can cause GVHD reside within the naïve T cell (TN) subset, and previous studies performed in mouse models and with human cells in vitro support this hypothesis. As a prelude to translating these findings to the clinic, we developed and evaluated a novel, two-step, clinically compliant procedure for manipulating peripheral blood stem cells (PBSC) to remove TN, preserve CD34+ hematopoietic stem cells, and provide for a fixed dose of memory T cells (TM) that includes T cells with specificity for common opportunistic pathogens encountered after HCT. Our studies demonstrate effective and reproducible performance of the immunomagnetic cell selection procedure for depleting TN. Moreover, after cell processing the CD45RA-depleted PBSC products are enriched for CD4+ and CD8+ TM with a central memory phenotype and contain TM cells that are capable of proliferating and producing effector cytokines in response to opportunistic pathogens.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 02/2014; · 3.15 Impact Factor
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    ABSTRACT: The migration of effector or memory T cells to the graft is a critical event in the rejection of transplanted organs. The prevailing view is that the key steps involved in T cell migration - integrin-mediated firm adhesion followed by transendothelial migration - are dependent on the activation of Gαi-coupled chemokine receptors on T cells. In contrast to this view, we demonstrated in vivo that cognate antigen was necessary for the firm adhesion and transendothelial migration of CD8+ effector T cells specific to graft antigens and that both steps occurred independent of Gαi signaling. Presentation of cognate antigen by either graft endothelial cells or bone marrow-derived APCs that extend into the capillary lumen was sufficient for T cell migration. The adhesion and transmigration of antigen-nonspecific (bystander) effector T cells, on the other hand, remained dependent on Gαi, but required the presence of antigen-specific effector T cells. These findings underscore the primary role of cognate antigen presented by either endothelial cells or bone marrow-derived APCs in the migration of T cells across endothelial barriers and have important implications for the prevention and treatment of graft rejection.
    The Journal of clinical investigation 05/2013; · 15.39 Impact Factor
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    ABSTRACT: Inbreeding depression and lack of genetic diversity in inbred mice could mask unappreciated causes of graft failure or remove barriers to tolerance induction. To test these possibilities, we performed heart transplantation between outbred or inbred mice. Unlike untreated inbred mice in which all allografts were rejected acutely (6-16 days posttransplantation), untreated outbred mice had heterogeneous outcomes, with grafts failing early (<4 days posttransplantation), acutely (6-24 days) or undergoing chronic rejection (>75 days). Blocking T cell costimulation induced long-term graft acceptance in both inbred and outbred mice, but did not prevent the early graft failure observed in the latter. Further investigation of this early phenotype established that it is dependent on the donor, and not the recipient, being outbred and that it is characterized by hemorrhagic necrosis and neutrophilic vasculitis in the graft without preformed, high titer antidonor antibodies in the recipient. Complement or neutrophil depletion prevented early failure of outbred grafts, whereas transplanting CD73-deficient inbred hearts, which are highly susceptible to ischemia-reperfusion injury, recapitulated the early phenotype. Therefore, outbred mice could provide broader insight into donor and recipient determinants of allograft outcomes but their hybrid vigor and genetic diversity do not constitute a uniform barrier to tolerance induction.
    American Journal of Transplantation 01/2013; · 6.19 Impact Factor
  • Kelli P Macdonald, Warren D Shlomchik, Pavan Reddy
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 01/2013; 19(1 Suppl):S10-4. · 3.15 Impact Factor
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    ABSTRACT: The efficacy of allogeneic hematopoietic stem cell transplantation is limited by graft-versus-host disease (GVHD). Host hematopoietic APCs are important initiators of GVHD, making them logical targets for GVHD prevention. Conventional dendritic cells (DCs) are key APCs for T cell responses in other models of T cell immunity, and they are sufficient for GVHD induction. However, we report in this article that in two polyclonal GVHD models in which host hematopoietic APCs are essential, GVHD was not decreased when recipient conventional DCs were inducibly or constitutively deleted. Additional profound depletion of plasmacytoid DCs and B cells, with or without partial depletion of CD11b(+) cells, also did not ameliorate GVHD. These data indicate that, in contrast with pathogen models, there is a surprising redundancy as to which host cells can initiate GVHD. Alternatively, very low numbers of targeted APCs were sufficient. We hypothesize the difference in APC requirements in pathogen and GVHD models relates to the availability of target Ags. In antipathogen responses, specialized APCs are uniquely equipped to acquire and present exogenous Ags, whereas in GVHD, all host cells directly present alloantigens. These studies make it unlikely that reagent-based host APC depletion will prevent GVHD in the clinic.
    The Journal of Immunology 03/2012; 188(8):3804-11. · 5.52 Impact Factor
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    ABSTRACT: Acute allograft rejection is dependent on adaptive immunity, but it is unclear whether the same is true for chronic rejection. Here we asked whether innate immunity alone is sufficient for causing chronic rejection of mouse cardiac allografts. We transplanted primarily vascularized cardiac grafts to recombinase activating gene-knockout (RAG(-/-)) mice that lack T and B cells but have an intact innate immune system. Recipients were left unmanipulated, received adjuvants that stimulate innate immunity, or were reconstituted with B-1 lymphocytes to generate natural IgM antibodies. In a second model, we transplanted cardiac allografts to mice that lack secondary lymphoid tissues (splenectomized aly/aly recipients) and studied the effect of NK cell inactivation on T cell-mediated chronic rejection. Acute cardiac allograft rejection was not observed in any of the recipients. Histological analysis of allografts harvested 50 to 90 days after transplantation to RAG(-/-) mice failed to identify chronic vascular or parenchymal changes beyond those observed in control syngeneic grafts. Chronic rejection of cardiac allografts parked in splenectomized aly/aly mice was observed only after the transfer of exogenously activated T cells. NK inactivation throughout the experiment, or during the parking period alone, reduced the severity of T cell-dependent chronic rejection. The innate immune system alone is not sufficient for causing chronic rejection. NK cells predispose healed allografts to T cell-dependent chronic rejection and may contribute to chronic allograft pathology.
    Transplant Immunology 03/2012; 26(2-3):113-8. · 1.52 Impact Factor
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    ABSTRACT: Recipient antigen-presenting cells (APCs) initiate GVHD by directly presenting host minor histocompatibility antigens (miHAs) to donor CD8 cells. However, later after transplantation, host APCs are replaced by donor APCs, and if pathogenic CD8 cells continue to require APC stimulation, then donor APCs must cross-present host miHAs. Consistent with this, CD8-mediated GVHD is reduced when donor APCs are MHC class I(-). To study cross-presentation, we used hosts that express defined MHC class I K(b)-restricted miHAs, crossed to K(b)-deficient backgrounds, such that these antigens cannot be directly presented. Cross-priming was surprisingly efficient, whether antigen was restricted to the hematopoietic or nonhematopoietic compartments. Cross-primed CD8 cells were cytolytic and produced IFN-γ. CD8 cells were exclusively primed by donor CD11c(+) cells, and optimal cross-priming required that they are stimulated by both type I IFNs and CD40L. In studying which donor APCs acquire host miHAs, we made the surprising discovery that there was a large-scale transfer of transmembrane proteins from irradiated hosts, including MHC class I-peptide complexes, to donor cells, including dendritic cells. Donor dendritic cells that acquired host MHC class I-peptide complexes were potent stimulators of peptide-specific T cells. These studies identify new therapeutic targets for GVHD treatment and a novel mechanism whereby donor APCs prime host-reactive T cells.
    Blood 09/2011; 118(24):6426-37. · 9.78 Impact Factor
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    ABSTRACT: Donor T cells contribute to the success of allogeneic hematopoietic stem cell transplantation (alloSCT). Alloreactive donor T cells attack leukemia cells, mediating the GVL effect. Donor T cells, including the memory T cells (T(M)) that are generated after infection, also promote immune reconstitution. Nonetheless, leukemia relapse and infection are major sources of treatment failure. Efforts to augment GVL and immune reconstitution have been limited by GVHD, the attack by donor T cells on host tissues. One approach to augmenting GVL has been to infuse ex vivo-generated T cells with defined specificities; however, this requires expertise that is not widely available. In the present study, we tested an alternative approach, adoptive immunotherapy with CD8+ T(M) from donors vaccinated against a single minor histocompatibility antigen (miHA) expressed by leukemia cells. Vaccination against the miHA H60 greatly augmented T(M)-mediated GVL against mouse chronic-phase (CP-CML) and blast crisis chronic myeloid leukemia (BC-CML). T(M)-mediated GVL was antigen specific and was optimal when H60 expression was hematopoietically restricted. Even when H60 was ubiquitous, donor H60 vaccination had a minimal impact on GVHD. T(M) from lymphocytic choriomeningitis virus (LCMV)-immune and H60-vaccinated donors augmented GVL and protected recipients from LCMV. These data establish a strategy for augmenting GVL and immune reconstitution without elaborate T-cell manipulation.
    Blood 09/2011; 118(22):5965-76. · 9.78 Impact Factor
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    ABSTRACT: Graft-versus-leukemia (GVL) against chronic-phase chronic myelogenous leukemia (CP-CML) is potent, but it is less efficacious against acute leukemias and blast-crisis chronic myelogenous leukemia (BC-CML). The mechanisms underlying GVL resistance are unknown. Previously, we found that alloreactive T cell targeting of GVL-sensitive bcr-abl-induced mouse CP-CML (mCP-CML) required TCR-MHC interactions and that multiple and redundant killing mechanisms were in play. To better understand why BC-CML is resistant to GVL, we performed a comprehensive analysis of GVL against mouse BC-CML (mBC-CML) induced by the retroviral transfer of the bcr-abl and NUP98/HOXA9 fusion cDNAs. Like human BC-CML, mBC-CML was GVL resistant, and this was not due to accelerated kinetics or a greater leukemia burden. To study T cell recognition and killing mechanisms, we generated a panel of gene-deficient leukemias by transducing bone marrow from gene-deficient mice. T cell target recognition absolutely required that mBC-CML cells express MHC molecules. GVL against both mCP-CML and mBC-CML required leukemia expression of ICAM-1. We hypothesized that mBC-CML would be resistant to some of the killing mechanisms sufficient to eliminate mCP-CML, but we found instead that the same mechanisms were effective against both types of leukemia, because GVL was similar against wild-type or mBC-CML genetically lacking Fas, TRAIL-R, Fas/TRAIL-R, or TNFR1/R2 or when donor T cells were perforin(-/-). However, mCP-CML, but not mBC-CML, relied on expression of programmed death-1 ligands 1 and 2 (PD-L1/L2) to resist T cell killing, because only GVL against mCP-CML was augmented when leukemias lacked PD-L1/L2. Thus, mBC-CML cells have cell-intrinsic mechanisms, distinct from mCP-CML cells, which protect them from T cell killing.
    The Journal of Immunology 08/2011; 187(4):1653-63. · 5.52 Impact Factor
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    ABSTRACT: Graft outcomes after kidney transplantation continue to be adversely affected by ischemia-reperfusion injury and rejection. High-resolution, real-time imaging of the transplanted kidney could shed valuable insights into these dynamic processes, but such methodology has not been established. Here we describe a technique for intravital imaging of the transplanted mouse kidney using multiphoton fluorescence microscopy. The technique enabled real-time, high-resolution imaging and quantitation of renal filtration, cell death, leukocyte adhesion and capillary blood flow after transplantation. Using this technique, we found that brief graft ischemia associated with the transplantation procedure led to a rapid decline in renal filtration accompanied by a significant increase in microvascular leakage and renal tubular epithelial cell death within the first 3 h after transplantation. No significant changes in leukocyte adhesion or capillary blood flow were observed during the same time period. This report establishes multiphoton fluorescence microscopy as a sensitive tool for simultaneously studying functional and structural perturbations that occur in the mouse kidney after transplantation and for investigating the migration of leukocytes to the graft.
    American Journal of Transplantation 08/2011; 11(10):2067-74. · 6.19 Impact Factor
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    ABSTRACT: Effector memory T cells (T(EM)) do not cause graft-versus-host disease (GVHD), though why this is has not been elucidated. To compare the fates of alloreactive naive (T(N)) or memory (T(M)) T cells, we developed a model of GVHD in which donor T cells express a transgene-encoded TCR specific for an antigenic peptide that is ubiquitously expressed in the recipient. Small numbers of naive TCR transgenic (Tg) T cells induced a robust syndrome of GVHD in transplanted recipients. We then used an established method to convert TCR Tg cells to T(M) and tested these for GVHD induction. This allowed us to control for the potentially different frequencies of alloreactive T cells among T(N) and T(M), and to track fates of alloreactive T cells after transplantation. T(EM) caused minimal, transient GVHD whereas central memory T cells (T(CM)) caused potent GVHD. Surprisingly, T(EM) were not inert: they, engrafted, homed to target tissues, and proliferated extensively, but they produced less IFN-γ and their expansion in target tissues was limited at later time points, and local proliferation was reduced. Thus, cell-intrinsic properties independent of repertoire explain the impairment of T(EM), which can initiate but cannot sustain expansion and tissue damage.
    Blood 07/2011; 118(23):6209-19. · 9.78 Impact Factor
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    ABSTRACT: Graft-versus-host disease (GVHD) caused by donor T cells attacking recipient tissues is a major cause of morbidity and mortality following allogeneic hematopoietic stem cell transplantation (alloSCT). Studies have shown that effector memory T (T(EM) ) cells do not cause GVHD but are capable of immune functions post-transplant, including graft-versus-leukemia (GVL) effects, but the reasons for this are unclear. In mice, the T(EM) pool may have a less diverse T-cell receptor (TCR) repertoire than naive T (T(N) ) cells with fewer alloreactive clones. We therefore tested whether enhancing the alloreactivity of T(EM) cells would restore their ability to cause GVHD. In an MHC-matched system, alloreactive T(EM) cells were created by transferring GVHD effector cells into syngeneic recipients and allowing conversion to T(EM) cells. Upon retransfer to freshly transplanted recipients, these cells caused only mild GVHD. Similarly, in an MHC-mismatched system, T(EM) cells with a proven increased precursor frequency of alloreactive clones only caused limited GVHD. Nonetheless, these same cells mounted strong in vitro alloresponses and caused rapid skin graft rejection. T(EM) cells created from CD4(+) T cells that had undergone lymphopenia-induced proliferation (LIP) also caused only mild GVHD. Our findings establish that conversion to T(EM) cells significantly reduces GVHD potency, even in cells with a substantially enhanced alloreactive repertoire.
    European Journal of Immunology 06/2011; 41(9):2782-92. · 4.97 Impact Factor
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    ABSTRACT: Rapamycin (Rapa), an immunosuppressive drug that acts through mammalian target of Rapa inhibition, broadly synergizes with tolerogenic agents in animal models of transplantation and autoimmunity. Rapa preferentially inhibits conventional CD4(+) Foxp3(-) T cells (Tconv) and promotes outgrowth of CD4(+)Foxp3(+) regulatory T cells (Treg) during in vitro expansion. Moreover, Rapa is widely perceived as augmenting both expansion and conversion of Treg in vivo. However, most quantitative studies were performed in lymphopenic hosts or in graft-versus-host disease models. We show in this study that in replete wild-type mice, Rapa significantly inhibits both homeostatic and alloantigen-induced proliferation of Treg, and promotes their apoptosis. Together, these lead to significant Treg depletion. Tconv undergo depletion to a similar degree, resulting in no change in the percent of Treg among CD4 cells. Moreover, in this setting, there was no evidence of conversion of Tconv into Treg. However, after withdrawal of Rapa, Treg recover Ag-induced proliferation more quickly than Tconv, leading to recovery to baseline numbers and an increase in the percent of Treg compared with Tconv. These findings suggest that the effects of Rapa on Treg survival, homeostasis, and induction, depend heavily on the cellular milieu and degree of activation. In vivo, the resistance of Treg to mammalian target of Rapa inhibition is relative and results from lymphopenic and graft-versus-host disease models cannot be directly extrapolated to settings more typical of solid organ transplantation or autoimmunity. Moreover, these results have important implications for the timing of Rapa therapy with tolerogenic agents designed to increase the number of Treg in vivo.
    The Journal of Immunology 03/2011; 186(5):2809-18. · 5.52 Impact Factor
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    ABSTRACT: Graft-versus-host disease (GVHD) is initiated by APCs that prime alloreactive donor T cells. In antipathogen responses, Ag-bearing APCs receive signals through pattern-recognition receptors, including TLRs, which induce the expression of costimulatory molecules and production of inflammatory cytokines, which in turn mold the adaptive T cell response. However, in allogeneic hematopoietic stem cell transplantation (alloSCT), there is no specific pathogen, alloantigen is ubiquitous, and signals that induce APC maturation are undefined. To investigate APC activation in GVHD, we used recipient mice with hematopoietic cells genetically deficient in pathways critical for APC maturation in models in which host APCs are absolutely required. Strikingly, CD8-mediated and CD4-mediated GVHD were similar whether host APCs were wild-type or deficient in MyD88, TRIF, or MyD88 and TRIF, which excludes essential roles for TLRs and IL-1β, the key product of inflammasome activation. Th1 differentiation was if anything augmented when APCs were MyD88/TRIF(-/-), and T cell production of IFN-γ did not require host IL-12. GVHD was also intact when APCs lacked the type I IFNR, which amplifies APC activation pathways that induce type I IFNs. Thus in GVHD, alloreactive T cells can be activated when pathways critical for antipathogen T cell responses are impaired.
    The Journal of Immunology 01/2011; 186(1):230-41. · 5.52 Impact Factor
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    ABSTRACT: Allogeneic bone marrow transplantation is an effective treatment for a number of malignant and nonmalignant diseases (Applebaum. 2001. Nature. 411: 385-389 and Copelan. 2006. N Engl J Med. 354: 1813-1826). However, the application of this therapeutic modality has been impeded by a number of confounding side effects, the most frequent and severe of which is the development of graft-versus-host disease (GVHD) (Copelan. 2006. N Engl J Med. 354: 1813-1826 and Blazar and Murphy. 2005. Philos Trans R Soc Lond B Biol Sci. 360: 1747-1767). Alloreactive donor T cells are critical for causing GVHD (Fowler. 2006. Crit Rev Oncol Hematol. 57: 225-244 and Ferrara and Reddy. 2006. Semin Hematol. 43: 3-10), whereas recent data demonstrated a significant role for the naturally occurring thymic-derived donor CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs) (Bluestone and Abbas. 2003. Nat Rev Immunol. 3: 253-257 and Shevach. 2006. Immunity. 25: 195-201) in suppressing experimental GVHD after bone marrow transplantation (Blazar and Taylor. 2005. Biol Blood Marrow Transpl. 11: 46-49 and Joffe and van Meerwijk. 2006. Semin Immunol. 18: 128-135) . Host APCs are required for induction of GVHD by the conventional donor T cells. However, it is not known whether they are also obligatory for donor Treg-mediated suppression of GVHD. Using multiple clinically relevant MHC-matched and -mismatched murine models of GVHD, we investigated the role of host APCs in the suppression of GVHD by donor Tregs. We found that alloantigen expression by the host APCs is necessary and sufficient for induction of GVHD protection by donor Tregs. This requirement was independent of their effect on the maintenance of Treg numbers and the production of IL-10 or IDO by the host APCs.
    The Journal of Immunology 10/2010; 185(7):3866-72. · 5.52 Impact Factor
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    ABSTRACT: Graft-versus-host disease (GVHD) is initiated and maintained by antigen-presenting cells (APCs) that prime alloreactive donor T cells. APCs are therefore attractive targets for GVHD prevention and treatment. APCs are diverse in phenotype and function, making understanding how APC subsets contribute to GVHD necessary for the development of APC-targeted therapies. Langerhans cells (LCs) have been shown to be sufficient to initiate skin GVHD in a major histocompatibility complex-mismatched model; however, their role when other host APC subsets are intact is unknown. To address this question, we used mice genetically engineered to be deficient in LCs by virtue of expression of diphtheria toxin A under the control of a BAC (bacterial artificial chromosome) transgenic hu-man Langerin locus. Neither CD8- nor CD4-mediated GVHD was diminished in recipients lacking LCs. Similarly, CD8- and CD4-mediated GVHD, including that in the skin, was unaffected if bone marrow came from donors that could not generate LCs, even though donor LCs engrafted in control mice. Engraftment of donor LCs after irradiation in wild-type hosts required donor T cells, with immunofluorescence revealing patches of donor and residual host LCs. Surprisingly, donor LC engraftment in Langerin-diphtheria toxin A (DTA) transgenic hosts was independent of donor T cells, suggesting that a Langerin(+) cell regulates repopulation of the LC compartment.
    Blood 10/2010; 117(2):697-707. · 9.78 Impact Factor
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    ABSTRACT: T cells present in lymphopenic environments undergo spontaneous (homeostatic) proliferation resulting in expansion of the memory T cell pool. Homeostatically generated memory T cells protect the host against infection but can cause autoimmunity and allograft rejection. Therefore, understanding the mechanisms that regulate homeostatic T cell proliferation is germane to clinical settings in which lymphodepletion is used. In this study, we asked whether NK cells, which regulate immune responses in lymphocyte-replete hosts, also regulate homeostatic T cell proliferation under lymphopenic conditions. We found that T cells transferred into genetically lymphocyte-deficient RAG-/- mice proliferate faster and generate more CD8+ memory T cells if NK cells were absent. CD8+ T cells that underwent homeostatic proliferation in the presence of NK cells generated mostly effector memory (CD44highCD62Llow) lymphocytes, whereas those that divided in the absence of NK cells were skewed toward central memory (CD44highCD62Lhigh). The latter originated predominantly from proliferation of the "natural" central memory CD8+ T cell pool. Regulation of homeostatic proliferation by NK cells occurred independent of perforin but was reversed by excess IL-15. Importantly, NK depletion enhanced CD8+ T cell recovery in T cell-depleted wild-type mice and accelerated rejection of skin allografts, indicating that regulation of homeostatic proliferation by NK cells is not restricted to genetically lymphocyte-deficient animals. These results demonstrate that NK cells downregulate homeostatic CD8+ T cell proliferation in lymphopenic environments by competing for IL-15. Concomitant NK and T cell depletion may be undesirable in transplant recipients because of enhanced expansion of memory CD8+ T cells that increase the risk of rejection.
    The Journal of Immunology 06/2010; 184(12):6649-57. · 5.52 Impact Factor
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    ABSTRACT: Hematopoietic malignant relapse still remains the major cause of death following allogeneic hematopoietic stem cell transplantation (HSCT). Although there has been a large focus on the immunologic mechanisms responsible for the graft-versus-tumor (GVT) effect or lack thereof, there has been little attention paid to investigating the biologic basis of hematologic malignant disease relapse following allogeneic HSCT. There are a large number of factors that are responsible for the biologic resistance of hematopoietic tumors following allogeneic HSCT. We have focused on 5 major areas including clonal evolution of cancer drug resistance, cancer radiation resistance, genomic basis of leukemia resistance, cancer epigenetics, and resistant leukemia stem cells. We recommend increased funding to pursue 3 broad areas that will significantly enhance our understanding of the biologic basis of malignant relapse after allogeneic HSCT, including: (1) genomic and epigenetic alterations, (2) cancer stem cell biology, and (3) clonal cancer drug and radiation resistance.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 03/2010; 16(6):709-28. · 3.15 Impact Factor

Publication Stats

4k Citations
443.30 Total Impact Points

Institutions

  • 2000–2014
    • Yale-New Haven Hospital
      • Department of Laboratory Medicine
      New Haven, Connecticut, United States
    • University of Pennsylvania
      • Department of Medicine
      Philadelphia, PA, United States
  • 2009–2013
    • University of Pittsburgh
      • • Thomas E. Starzl Transplantation Institute
      • • Department of Surgery
      Pittsburgh, Pennsylvania, United States
  • 2003–2012
    • Yale University
      • • Yale Cancer Center
      • • School of Medicine
      • • Department of Immunobiology
      • • Department of Laboratory Medicine
      New Haven, CT, United States
  • 2011
    • Comprehensive Cancer Centers of Nevada
      Las Vegas, Nevada, United States
  • 2008–2009
    • Penn State Hershey Medical Center and Penn State College of Medicine
      • Department of Medicine
      Hershey, PA, United States
  • 1996–1999
    • Hospital of the University of Pennsylvania
      • • Department of Medicine
      • • Division of Hematology/Oncology
      Philadelphia, Pennsylvania, United States