T Cells Motility in the Colonic Gvhd Is Influenced By Both Cognate Interaction and Microenvironment

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3346-3346
Author(s):  
Jieqing Zhu ◽  
Cassandra Secunda ◽  
Michael Parrish ◽  
David Gonzalez ◽  
Ann Haberman ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Cell Motility ◽  
Conflicts Of Interest ◽  
Allogeneic Bone Marrow Transplantation ◽  
Allogeneic Bone ◽  
Cd4 Cells ◽  
Cd8 Cells ◽  
Cell Stability

Abstract Graft-versus-host disease (GVHD) accounts for substantial morbidity and mortality after allogeneic bone marrow transplantation. Allograft T cells are stimulated by both host and donor-derived antigen presenting cells (APCs). After differentiating into T effector cells, donor T cells migrate to GVHD target organs where they mediate damage directly and indirectly. However, very little is known about the dynamics of T cells in GVHD target tissues and how their behaviors are affected by the local environments, including by tissue-resident APCs. We utilized two-photon intravital microscopy (2PIM) to analyze T cell locations, motility and interactions with APCs. 129S1/SVLmJ (129) (H-2b) hosts were irradiated and reconstituted with C57Bl/6 (B6) (H-2b) CD11-YFP transgenic mice bone marrow together with B6 dsRed (RFP) CD8 cells and cyan fluorescent protein (CFP) CD4 cells. Mice were imaged from days 25-42 post-transplant. We focused on the colon which is strongly targeted in this model and in humans and which previously has been difficult to image by 2PIM. In syngeneic B6 into B6 recipients, donor CD11c+, CD8+ and CD4+ cells populate the colonic mucosa. However, a greater number of cells accumulated in the allogenic as compared to syngeneic recipients. Based on the analysis of 7-8 mice per group, T cells in allogenic mice were less motile. The mean CD8 speeds in syngeneic and allogeneic mice were 3.38 ± 0.07 µm/min and 2.21 ± 0.03 µm/min, respectively. Mean CD4 speeds in syngeneic and allogeneic mice were 3.11 ± 0.08 µm/min and 2.38 ± 0.04 µm/min, respectively. The majority of T cells were stationary, with few entering or leaving the imaged volume. Perfusion was confirmed by i.v. rhodamine-dextran; therefore, stationary behaviors was not due to tissue viability. Using optical clearing we imaged whole-mount colonic tissue from mucosa to serosa. T cells were aggregated in the sub-mucosa and infiltrated crypts and surprisingly also the muscular layer. Ki67+ T cells were found throughout, especially in the submucosa. Given the 2PIM data which show few new T cells entering the imaged volumes, these cells were likely stimulated to divide locally. Preliminary data with EdU pulsing suggest this to be the case. To determine whether T cell stability is microenvironment- or antigen-driven, we injected OT-1 TCR transgenic effectors which do not recognize any antigen in the recipient and imaged the next day. Most colonic OT-1 cells showed the same stationary behavior as nearby donor-derived CD4 and CD8 cells, suggesting that factors in the GVHD colon microenvironment drive T cell stability. Nonetheless there was also an antigen-driven component as injection of an anti-MHCII antibody (but not isotype control Ab) increased CD4+ T cell motility presumably by disrupting TCR:MHCII interaction. These results show the motility of T cells in the GVHD colon is influence by both TCR:MHC cognate interactions and by the microenvironment. That T cells are dividing and may be activated in situ, suggesting GVHD may be maintained locally. Current studies are focusing on what antigen-independent factors affect T cell motility and on defining the roles played by tissue APCs. Disclosures No relevant conflicts of interest to declare.

scholarly journals Keratinocyte growth factor enhances DNA plasmid tumor vaccine responses after murine allogeneic bone marrow transplantation

Blood ◽  
2009 ◽  
Vol 113 (7) ◽  
pp. 1574-1580 ◽  
Author(s):  
Robert R. Jenq ◽  
Christopher G. King ◽  
Christine Volk ◽  
David Suh ◽  
Odette M. Smith ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Keratinocyte Growth Factor ◽  
Allogeneic Bone Marrow Transplantation ◽  
Allogeneic Bone ◽  
Effector Cells ◽  
Cd8 Cells ◽  
T Cell Reconstitution ◽  
Dna Plasmid

Abstract Keratinocyte growth factor (KGF), which is given exogenously to allogeneic bone marrow transplantation (allo-BMT) recipients, supports thymic epithelial cells and increases thymic output of naive T cells. Here, we demonstrate that this improved T-cell reconstitution leads to enhanced responses to DNA plasmid tumor vaccination. Tumor-bearing mice treated with KGF and DNA vaccination have improved long-term survival and decreased tumor burden after allo-BMT. When assayed before vaccination, KGF-treated allo-BMT recipients have increased numbers of peripheral T cells, including CD8+ T cells with vaccine-recognition potential. In response to vaccination, KGF-treated allo-BMT recipients, compared with control subjects, generate increased numbers of tumor-specific CD8+ cells, as well as increased numbers of CD8+ cells producing interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α). We also found unanticipated benefits to antitumor immunity with the administration of KGF. KGF-treated allo-BMT recipients have an improved ratio of T effector cells to regulatory T cells, a larger fraction of effector cells that display a central memory phenotype, and effector cells that are derived from a broader T-cell–receptor repertoire. In conclusion, our data suggest that KGF can function as a potent vaccine adjuvant after allo-BMT through its effects on posttransplantation T-cell reconstitution.

Recipient CD8+ DC Delete Alloreactive Donor CTL and Promote Leukemic Relapse after Allogeneic BMT

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4279-4279
Author(s):  
Kate A Markey ◽  
Rachel D Kuns ◽  
Renee J Robb ◽  
Motoko Koyama ◽  
Kate Helen Gartlan ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Antigen Presentation ◽  
Median Survival ◽  
Conflicts Of Interest ◽  
Critical Role ◽  
Allogeneic Bone Marrow Transplantation ◽  
Allogeneic Bone ◽  
Leukemic Relapse

Abstract Allogeneic bone marrow transplantation (BMT) remains the therapy of choice for many haematological malignancies, but despite the curative benefit of the immunological graft-versus-leukemia (GVL) effect, relapse remains a key cause of death. We have investigated the role of recipient dendritic cells (DC) in antigen presentation to donor CD8 cytotoxic T cells (CTL) in a model of BMT where GVHD and GVL are directed to multiple minor histocompatibility antigens (mHA) and survival reflects GVL activity. C3H.Sw bone marrow and purified CD8 T cell grafts were transplanted with B6-derived MLL-AF9 induced primary acute myeloid leukemia (AML) into lethally irradiated B6.CD11c.DOG recipients (diphtheria toxin receptor (DTR), ovalbumin and GFP expression driven off the CD11c promoter) such that recipient DC can be deleted by DT administration. Surprisingly, depletion of recipient DC resulted in improved leukemic control (median survival 43 vs 31 days, P <0.001). The use of IRF8-/- BMT recipients (in which the CD8+ DC subset is absent) confirmed that recipient CD8+ DC were critical for regulating these GVL effects (median survival 43 vs 34 days, P = 0.0005). Conversely, when recipient CD8+ DC were expanded in a B6 to B6D2F1 model with bcr-abl/Nup98-HoxA9 induced primary AML, by using Flt3-L treatment for 10 days prior to BMT, GVL effects were completely eliminated, rendering relapse rate equivalent to that seen in the recipients of T cell depleted (TCD) grafts (median survival 11 days in BM+T and TCD groups where recipients were pre-treated with Flt3-L, vs. >45 days in the saline treated BM+T group). The use of B6.CD11c-Rac1 transgenic BMT recipients (who cannot process and present exogenously acquired antigen) confirmed that this effect was the result of endogenous alloantigen presentation by recipient DC and independent of cross-presentation.Using the same depletion strategies in an antigen-specific model (with donor OT-I T cells and B6.CD11c.DOG x DBA/2 F1 recipients) we confirmed that recipient DC invoked effector donor CTL activation, differentiation (CD25+ CD69+ CD62L-) and subsequent apoptosis (as measured by Annexin V; 52.4% vs. 23.9% in DC replete vs. depleted recipients, P = 0.01). There was a consequent profound contraction of the donor CTL compartment by day 10 in DC replete recipients. This contraction of the CTL compartment was associated with reduced expression of the cytolytic molecule granzyme B (MFI 1922 vs 1097, P = 0.02). Antigen presentation has a critical role in the initiation of donor T cell alloreactivity and GVL after BMT. Here we demonstrate that endogenous alloantigen presentation by recipient CD8+ DC to donor T cells leads to activation induced death of donor CTL early after BMT, which in turn facilitates leukemic relapse. This concept has critical implications for the design of therapies that target DC in the peri-transplant period and confirms that recipient DC regulate GVL effects. Disclosures No relevant conflicts of interest to declare.

scholarly journals Imbalances within the peripheral blood T-helper (CD4+) and T-suppressor (CD8+) cell populations in the reconstitution phase after human bone marrow transplantation

Blood ◽  
1988 ◽  
Vol 71 (5) ◽  
pp. 1196-1200 ◽  
Author(s):  
A Velardi ◽  
A Terenzi ◽  
S Cucciaioni ◽  
R Millo ◽  
CE Grossi ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Bone Marrow Transplantation ◽  
T Cell ◽  
Peripheral Blood ◽  
Marrow Transplantation ◽  
Allogeneic Bone Marrow Transplantation ◽  
T Cell Subsets ◽  
Allogeneic Bone ◽  
T Helper

Abstract Peripheral blood T cell subsets were evaluated in 11 patients during the reconstitution phase after allogeneic bone marrow transplantation and compared with 11 age-matched controls. The proportion of cells coexpressing Leu7 and CD11b (C3bi receptor) markers was determined within the CD4+ (T-helper) and the CD8+ (T-suppressor) subsets by two- color immunofluorescence analysis. CD4+ and CD8+ T cells reached normal or near-normal values within the first year posttransplant. In contrast to normal controls, however, most of the cells in both subsets coexpressed the Leu7 and CD11b markers. T cells with such phenotype display the morphological features of granular lymphocytes (GLs) and a functional inability to produce interleukin 2 (IL 2). These T cell imbalances were not related to graft v host disease (GvHD) or to clinically detectable virus infections and may account for some defects of cellular and humoral immunity that occur after bone marrow transplantation./

scholarly journals Different T-cell receptor repertoires between lesions and peripheral blood in acute graft-versus-host disease after allogeneic bone marrow transplantation

Blood ◽  
1996 ◽  
Vol 87 (7) ◽  
pp. 3019-3026 ◽  
Author(s):  
K Kubo ◽  
K Yamanaka ◽  
H Kiyoi ◽  
H Fukutani ◽  
M Ito ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Bone Marrow Transplantation ◽  
T Cell ◽  
T Cell Receptor ◽  
Allogeneic Bone Marrow Transplantation ◽  
Cell Receptor ◽  
Allogeneic Bone ◽  
Graft Versus Host ◽  
Acute Graft

From the viewpoint of T-cell receptor (TCR) repertoire, we studied the role of T cells in acute graft-versus-host disease (GVHD) after allogeneic bone marrow transplantation (allo-BMT) from an HLA-identical sibling. By means of inverse polymerase chain reaction method and DNA sequencing, we analyzed TCR-alpha and -beta transcripts from GVHD lesions and peripheral blood (PB) in a patient with typical GVHD together with PB from donor. At the initial onset of GVHD, V alpha-7 and -19 subfamilies were oligoclonally expanded in the PB compared with those in the oral mucosal lesions. At the second onset, V alpha-2, and V beta-6 subfamilies were more frequently detected in the cutaneous lesion than in the PB. Some TCR transcripts were recurrently found either in the mucosal or cutaneous lesions (or in both) and not in the PB. Furthermore, some of recurrent TCR transcripts in the lesions shared V gene segments and common motifs of complementarity determining region-3. These findings suggested that T cells infiltrating the GVHD lesions recognized a limited kind of antigens presented by patient's tissues with GVHD, and that T-cell repertoire in the GVHD lesions was different from that in the PB.

scholarly journals T-cell ontogeny after autologous bone marrow transplantation: failure to synthesize interleukin-2 (IL-2) and lack of CD2- and CD3-mediated proliferation by both CD4- and CD8+ cells even in the presence of exogeneous IL-2

Blood ◽  
1989 ◽  
Vol 74 (6) ◽  
pp. 2270-2277 ◽  
Author(s):  
S Cayeux ◽  
S Meuer ◽  
A Pezzutto ◽  
M Korbling ◽  
R Haas ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Autologous Bone Marrow Transplantation ◽  
Interleukin 2 ◽  
Autologous Bone Marrow ◽  
Cd4 Cells ◽  
Cd8 Cells ◽  
Autologous Bone ◽  
Cell Ontogeny

Abstract T cells generated during a second round of ontogeny after autologous bone marrow transplantation (ABMT) represent a unique model of early T- cell ontogeny in an autologous situation. Since grafted bone marrows were pretreated in vitro with the cyclophosphamide derivative ASTA Z 7557, circulating T cells had to be regenerated from reinfused hematopoietic progenitor cells. The T-cell population derived from 25 patients post-ABMT was phenotypically characterized: an increase in CD8+ cells, a low percentage of CD4+ cells, and a median of 12% CD56+ (NKH1+) cells were found. When the T cells were stimulated with phytohemagglutinin (PHA) and phorbol myristate acetate (PMA), defective interleukin-2 (IL-2) secretion was observed. In addition, proliferative responses of the T cells after activation through the antigen-receptor- dependent CD3 pathway, through the CD2 dependent alternative T-cell pathway, and by the lectin PHA were investigated. Despite the presence of CD2, CD3, alpha/beta chains of the T-cell receptor, and CD25+ IL-2 surface receptors, abnormal proliferative responses were obtained even in the presence of exogeneous IL-2. In experiments where the T-cell population was separated into CD4+ cells and CD8+ cells, both the CD4- and CD8+ subsets were unable to respond to activating and proliferating signals. Thus, T cells at early stages of ontogeny not only possess an intrinsic defect in IL-2 synthesis but, in addition, were unable to express functional IL-2 receptors in response to mitogenic stimuli.

Donor CD4+CD25+ T Cells Require Syngeneic MHC Class II for Initial Support of MHC-Mismatched Hematopoietic Engraftment.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 251-251 ◽  
Author(s):  
Alan Hanash ◽  
Robert B. Levy
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Mhc Class Ii ◽  
Allogeneic Bone Marrow Transplantation ◽  
Class Ii ◽  
Allogeneic Bone ◽  
Inherited Disorders ◽  
Donor Chimerism

Abstract Despite the potential to cure both acquired and inherited disorders involving the hematopoietic compartment, application of allogeneic bone marrow transplantation (BMT) is limited by the frequent and severe outcome of Graft vs. Host Disease (GVHD). Unfortunately, efforts to reduce GVHD by purging the donor graft of T cells have resulted in poor engraftment and elevated disease recurrence. Alternative cell populations capable of supporting allogeneic engraftment without inducing GVHD could increase the potential for donor-recipient matching and decrease treatment associated risks. We have observed that GVHD-suppressive donor CD4+CD25+ T cells are capable of supporting allogeneic hematopoietic engraftment, as demonstrated by initial donor progenitor activity and long-term chimerism and tolerance. Using a murine MHC mismatched model transplanting 0.5–2x106 GFP+ C57BL/6 (B6) T cell-depleted bone marrow cells into 7.0 Gy sublethally irradiated BALB/c recipients, splenic CFU assessment demonstrated that co-transplantation of 1x106 B6 CD4+CD25+ T cells lead to increased donor lineage-committed GM (p&lt;.01) and multi-potential HPP (p&lt;.05) progenitors seven days post-BMT compared to transplantation of BM alone. Furthermore, co-transplantation of CD4+CD25+ T cells lead to lymphoid and myeloid chimerism in peripheral blood (lineage specific mean donor chimerism ± SE: B220, 67.7±15.2 vs. 0.3±0.3; CD4, 38.3±10.5 vs.0.9±0.9; CD8, 48.3±11.0 vs. 1.0±1.0; Mac-1, 58.8±16.5 vs. 0.3±0.3) and the presence of donor GM and HPP progenitors in recipient marrow two months post-BMT (mean CFU chimerism ± SE: CFU-GM, 54.5±12.8 vs. 0.0; CFU-HPP, 63.0±17.8 vs.0.0). Donor chimerism persisted six months post-BMT and was associated with tolerance to donor and host antigens by acceptance of donor and host skin grafts &gt;50 days post-homotopic grafting. Characterization of the initial invents of engraftment support demonstrated that augmentation of donor progenitors did not require CD4+CD25+ T cell IL-10, as co-transplantation of B6-wt and B6-IL-10−/− CD4+CD25+ T cells both significantly increased total CFU-GM (mean CFU±SE: BM alone, 657.5±248.2; BM + wt, 1972±331.5; BM + IL-10−/−, 1965±401.7; both p&lt;.05 vs. BM alone). Assessment of the antigenic requirements for activation of progenitor support demonstrated that donor CD4+CD25+ T cells did not require alloreactivity to support progenitors, as BALB/c x B6 F1 CD4+CD25+ T cells significantly increased B6 CFU-GM in BALB/c recipients (p&lt;.001 vs. BM alone). However, B6 CD4+CD25+ T cells failed to augment C3H/HeJ CFU-GM in BALB/c recipients (p&gt;.05 vs. BM alone), suggesting that donor CD4+CD25+ T cells might require recognition of syngeneic MHC for progenitor support. Indeed, augmentation of donor CFU-GM was abrogated when B6 CD4+CD25+ T cells were co-transplanted with B6-MHC class II−/− marrow into BALB/c recipients (p&gt;.05 vs. BM alone). In conclusion, donor CD4+CD25+ T cells capable of promoting long-term engraftment and tolerance do not require IL-10 for support of initial donor progenitor activity, however progenitor support does require co-transplantation with syngeneic MHC class II expressing marrow. Donor CD4+CD25+ T cells may thus represent a useful alternative to unfractionated T cells for promotion of engraftment following allogeneic hematopoietic transplantation.

Deletion Of Fanca Or Fancd2 Dysregulates Treg Activity and Exacerbates Gvhd In Mice

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3239-3239
Author(s):  
Wei Du ◽  
Ozlem Erden ◽  
Andrew Wilson ◽  
Jared Sipple ◽  
Jonathan Schick ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Transcriptional Activity ◽  
Conflicts Of Interest ◽  
Bone Marrow Failure ◽  
Genetic Disorder ◽  
Allogeneic Bone Marrow Transplantation ◽  
Allogeneic Bone ◽  
In Vitro Proliferation

Abstract Fanconi anemia (FA) is a genetic disorder associated with bone marrow failure and leukemia. Recent studies demonstrate fundamental immune defects in FA. However, the mechanisms that are critical for FA immunodeficiency are not known. Here we report that deletion of Fanca or Fancd2 dysregulates the suppressive activity of regulatory T cells (Tregs) and exacerbates graft-versus-host disease (GVHD) in mice. Recipient mice of Fanca-/- or Fancd2-/- bone marrow chimeras exhibited severe acute GVHD after allogeneic bone marrow transplantation (BMT). Further study showed that T cells from Fanca-/- or Fancd2-/- mice induced higher GVHD lethality than those from WT littermates. Mechanistically, FA Tregs possessed lower proliferative suppression potential compared to WT Tregs, as demonstrated by in vitro proliferation assay and BMT. Analysis of CD25+Foxp3+ Tregs indicated that loss of Fanca or Fancd2 dysregulated Foxp3 transcriptional activity. Additionally, CD25+Foxp3+ Tregs of Fanca-/- or Fancd2-/- mice were less efficient in suppressing the production of GVHD-associated inflammatory cytokines. Consistently, incremental NF-kB transcriptional activity was observed in infiltrated T cells from FA GVHD mice. Conditional deletion of p65 in FA Tregs desreased GVHD mortality. Our study uncovers an essential role for the FA proteins in maintaining Treg homeostasis and suggests that targeted blocking NF-kB signaling within T cells represents an attractive therapeutic strategy to ameliorate GVHD in FA. Disclosures: No relevant conflicts of interest to declare.

T-Cell Immune Reconstitution in Pediatric Leukemia Patients After Allogeneic Bone Marrow Transplantation With T-Cell–Depleted or Unmanipulated Grafts: Evaluation of Overall and Antigen-Specific T-Cell Repertoires

Blood ◽  
1999 ◽  
Vol 94 (12) ◽  
pp. 4358-4369 ◽  
Author(s):  
Barbara C. Godthelp ◽  
Maarten J.D. van Tol ◽  
Jaak M. Vossen ◽  
Peter J. van den Elsen
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Bone Marrow Transplantation ◽  
T Cell ◽  
Marrow Transplantation ◽  
Immune Reconstitution ◽  
Allogeneic Bone Marrow Transplantation ◽  
Cell Selection ◽  
Allogeneic Bone ◽  
T Cell Selection

To evaluate the role of T-cell selection in the thymus and/or periphery in T-cell immune reconstitution after allogeneic bone marrow transplantation (allo-BMT), we have analyzed the overall and antigen-specific T-cell repertoires in pediatric allo-BMT recipients treated for leukemia. We observed a lack of overall T-cell receptor (TCR) diversity in the repopulating T cells at 3 months after allo-BMT, as was deduced from complementarity determining region 3 (CDR3) size distribution patterns displaying reduced complexity. This was noted particularly in recipients of a T-cell–depleted (TCD) graft and, to a lesser extent, also in recipients of unmanipulated grafts. At 1 year after allo-BMT, normalization was observed of TCR CDR3 size complexity in almost all recipients. Analysis of the antigen-specific T-cell repertoire at 1 year after BMT showed that the T cells responding to tetanus toxoid (TT) differed in TCR gene segment usage and in amino acid composition of the CDR3 region when comparing the recipient with the donor. Moreover, the TT-specific TCR repertoire was found to be stable within a given allo-BMT recipient, because TT-specific T cells with completely identical TCRs were found at 3 consecutive years after transplantation. These observations suggest an important role for T-cell selection processes in the complete restoration of the T-cell immune repertoire in children after allo-BMT.

scholarly journals Donor T-cell alloreactivity against host thymic epithelium limits T-cell development after bone marrow transplantation

Blood ◽  
2007 ◽  
Vol 109 (9) ◽  
pp. 4080-4088 ◽  
Author(s):  
Mathias M. Hauri-Hohl ◽  
Marcel P. Keller ◽  
Jason Gill ◽  
Katrin Hafen ◽  
Esther Pachlatko ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Bone Marrow Transplantation ◽  
T Cell ◽  
Marrow Transplantation ◽  
Allogeneic Bone Marrow Transplantation ◽  
Allogeneic Bone Marrow ◽  
Thymic Epithelial Cells ◽  
Allogeneic Bone ◽  
Donor T Cells

Abstract Acute graft-versus-host disease (aGVHD) impairs thymus-dependent T-cell regeneration in recipients of allogeneic bone marrow transplants through yet to be defined mechanisms. Here, we demonstrate in mice that MHC-mismatched donor T cells home into the thymus of unconditioned recipients. There, activated donor T cells secrete IFN-γ, which in turn stimulates the programmed cell death of thymic epithelial cells (TECs). Because TECs themselves are competent and sufficient to prime naive allospecific T cells and to elicit their effector function, the elimination of host-type professional antigen-presenting cells (APCs) does not prevent donor T-cell activation and TEC apoptosis, thus precluding normal thymopoiesis in transplant recipients. Hence, strategies that protect TECs may be necessary to improve immune reconstitution following allogeneic bone marrow transplantation.

scholarly journals Peripheral deletional tolerance of alloreactive CD8 but not CD4 T cells is dependent on the PD-1/PD-L1 pathway

Blood ◽  
2008 ◽  
Vol 112 (5) ◽  
pp. 2149-2155 ◽  
Author(s):  
Fabienne Haspot ◽  
Thomas Fehr ◽  
Carrie Gibbons ◽  
Guiling Zhao ◽  
Timothy Hogan ◽  
...  
Keyword(s):  
T Cell ◽  
Allogeneic Bone Marrow Transplantation ◽  
Cell Receptor ◽  
Allogeneic Bone ◽  
Cd4 Cells ◽  
Activation Markers ◽  
Cd8 Cells ◽  
Cd8 Cell ◽  
Cd4 Help ◽  
Total Body

Abstract Although interaction between programmed death-1 (PD-1) and the ligand PD-L1 has been shown to mediate CD8 cell exhaustion in the setting of chronic infection or the absence of CD4 help, a role for this pathway in attenuating early alloreactive CD8 cell responses has not been identified. We demonstrate that the PD-1/PD-L1 pathway is needed to rapidly tolerize alloreactive CD8 cells in a model that requires CD4 cells and culminates in CD8 cell deletion. This protocol involves allogeneic bone marrow transplantation (BMT) following conditioning with low-dose total body irradiation and anti-CD154 antibody. Tolerized donor-reactive T-cell receptor transgenic CD8 cells are shown to be in an abortive activation state prior to their deletion, showing early and prolonged expression of activation markers (compared with rejecting CD8 cells) while being functionally silenced by day 4 after transplantation. Although both tolerized and rejecting alloreactive CD8 cells up-regulate PD-1, CD8 cell tolerance is dependent on the PD-1/PD-L1 pathway. In contrast, CD4 cells are tolerized independently of this pathway following BMT with anti-CD154. These studies demonstrate a dichotomy between the requirements for CD4 and CD8 tolerance and identify a role for PD-1 in the rapid tolerization of an alloreactive T-cell population via a deletional mechanism.

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