Differentiation of a CD4+/CD8αβ+ Double Positive T Cell Population From The CD8 Pool Is Sufficient To Mediate Graft-vs-Host Disease but not Graft-vs-Leukemia Effects

Acute graft-vs-host disease (aGVHD) and tumor relapse remain the primary complications following allogeneic hematopoietic stem cell transplantation (allo-HSCT) for malignant blood disorders. While post-transplant cyclophosphamide has reduced the overall prevalence and severity of aGVHD, relapse rates remain a concern. Thus, there remains a need to identify the specific human T cell subsets mediating GVHD pathology versus graft-versus-leukemia (GVL) effects. In xenogeneic transplantation studies using primary human cells from a variety of donors and tissue sources, we observed the development of a mature CD4+/CD8αβ+ double positive T cell (DPT) population in mice succumbing to lethal aGVHD but not in mice that failed to develop aGVHD. The presence of DPT, irrespective of graft source, was predictive of lethal GVHD as early as one week after xenogeneic transplantation. DPT co-express the master transcription factors of the CD8 and CD4 lineages, RUNX3 and THPOK respectively, and produce both cytotoxic and modulatory cytokines. To identify the origin of DPT, we transplanted isolated human CD4 or CD8 T cells, which in turn revealed that DPT only arise from the CD8 pool. Interestingly, re-transplantation of sorted CD8 T cells from GVHD mice did not reveal a second wave of DPT differentiation. Re-transplantation of flow-sorted DPT, CD8 or CD4 T cells from GVHD mice revealed that DPT are sufficient to mediate GVHD pathology but not GVL effects versus B-cell acute lymphoblastic leukemia. Lastly, we confirmed the presence and correlation of DPT with aGVHD pathology in a small cohort of allo-HSCT patients that developed grade 2-4 aGVHD in our clinic. Further understanding of DPT differentiation and pathology may lead to targeted prophylaxis and/or treatment regimens for aGVHD and potentially other human chronic inflammatory diseases.

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549 Characterizing double positive T cells in the tumor microenvironment: a tale of promiscuous cell fates

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0549 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A586-A586

Author(s):

Sara Schad ◽

Andrew Chow ◽

Heng Pan ◽

Levi Mangarin ◽

Roberta Zappasodi ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Tumor Microenvironment ◽

Cd8 T Cells ◽

Human Melanoma ◽

B16 Melanoma ◽

T Cell Subsets ◽

Double Positive ◽

Cell Fates ◽

Single Positive

BackgroundCD4 and CD8 T cells are genetically and functionally distinct cell subsets of the adaptive immune system that play pivotal roles in immune surveillance and disease control. During development in the thymus, transcription factors ThPOK and Runx3 regulate the differentiation and maturation of these two lineages into single positive T cells that enter the periphery with mutually exclusive expression of either the CD4 or CD8 co-receptor.1–2 Despite our expectation that these two cell fates are fixed, mature CD4+CD8+ double positive (DP) T cells have been described in the context of numerous immunological responses, including cancer, but their molecular and functional properties and therapeutic relevance remain controversial and largely unknown.3–5MethodsOur lab has identified and characterized a heterogenous DP T cell population in murine and human melanoma tumors comprised of CD4 and CD8 T cells re-expressing the opposite co-receptor and a parallel uptake in the opposite cell type’s phenotype and function. Using CD4 (Trp1) and CD8 (Pmel) transgenic TCR T cells specific to B16 melanoma antigens gp75 and gp100 respectively, we demonstrate the re-expression of the opposite co-receptor following adoptive T cell transfer in B16 melanoma tumor bearing mice.ResultsSpecifically, up to 50% of transferred CD4 Trp1 T cells will re-express CD8 to become a DP T cell in the tumor microenvironment. Further, these CD4 derived DP T cells upregulate CD8 lineage regulator Runx3 and cytolytic genes Gzmb, Gzmk, and Prf1 to become potent cytotoxic T cells. Alternatively, a subset of CD8 Pmel T cells differentiate into DP T cells characterized by the increased expression of CD4, ThPOK, and regulatory marker FoxP3 (figure 1). In addition, we utilized 10x single cell and ATAC sequencing to further characterize these divergent DP T cell populations among open repertoire T cells isolated from murine and human melanoma tumors.ConclusionsOur findings highlight the capability of single positive T cells to differentiate in response to antigen and local stimuli into novel T cell subsets with polyfunctional characteristics. The resulting cell subsets will potentially affect the tumor microenvironment in distinct ways. Our studies may inform therapeutic approaches to identify antigen specific T cells as well as innovative signaling pathways to target when genetically engineering T cells to optimize cytotoxic function in the setting of adoptive cell therapy.Ethics ApprovalThe human biospecimen analyses were approved by Memorial Sloan Kettering Cancer Center IRB #06-107ReferencesEllmeier W, Haust L & Tschismarov R. Transcriptional control of CD4 and CD8 coreceptor expression during T cell development. Cell Mol Life Sci 2013;70:4537–4553.Luckey MA, et al. The transcription factor ThPOK suppresses Runx3 and imposes CD4+ lineage fate by inducing the SOCS suppressors of cytokine signaling. Nature Immunology 2014; 15, 638–645.Bohner P, et al. Double positive CD4(+)CD8(+) T Cells are enriched in urological cancers and favor T Helper-2 polarization. Front Immunol 2019; 10, 622.Nascimbeni M, Shin E-C, Chiriboga L, Kleiner DE & Rehermann B. Peripheral CD4(+)CD8(+) T cells are differentiated effector memory cells with antiviral functions. Blood 2004;104:478–486.Nishida K, et al. Clinical importance of the expression of CD4+CD8+ T cells in renal cell carcinoma. Int Immunol 2020;32:347–357.

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Specific expression of the human CD4 gene in mature CD4+ CD8- and immature CD4+ CD8+ T cells and in macrophages of transgenic mice

Molecular and Cellular Biology ◽

10.1128/mcb.14.2.1084-1094.1994 ◽

1994 ◽

Vol 14 (2) ◽

pp. 1084-1094

Author(s):

Z Hanna ◽

C Simard ◽

A Laperrière ◽

P Jolicoeur

Keyword(s):

T Cells ◽

T Cell ◽

Transgenic Mice ◽

Cd8 T Cells ◽

Transcription Initiation ◽

Critical Role ◽

Regulatory Elements ◽

T Cell Subsets ◽

Double Positive ◽

Specific Expression

The CD4 protein plays a critical role in the development and function of the immune system. To gain more insight into the mechanism of expression of the human CD4 gene, we cloned 42.2 kbp of genomic sequences comprising the CD4 gene and its surrounding sequences. Studies with transgenic mice revealed that a 12.6-kbp fragment of the human CD4 gene (comprising 2.6 kbp of 5' sequences upstream of the transcription initiation site, the first two exons and introns, and part of exon 3) contains the sequences required to support the appropriate expression in murine mature CD4+ CD8- T cells and macrophages but not in immature double-positive CD4+ CD8+ T cells. Expression in CD4+ CD8+ T cells was found to require additional regulatory elements present in a T-cell enhancer fragment recently identified for the murine CD4 gene (S. Sawada and D. R. Littman, Mol. Cell. Biol. 11:5506-5515, 1991). These results suggest that expression of CD4 in mature and immature T-cell subsets may be controlled by distinct and independent regulatory elements. Alternatively, specific regulatory elements may control the expression of CD4 at different levels in mature and immature T-cell subsets. Our data also indicate that mouse macrophages contain the regulatory factors necessary to transcribe the human CD4 gene.

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TCF-1 limits the formation of Tc17 cells via repression of the MAF–RORγt axis

Journal of Experimental Medicine ◽

10.1084/jem.20181778 ◽

2019 ◽

Vol 216 (7) ◽

pp. 1682-1699 ◽

Cited By ~ 19

Author(s):

Lisa A. Mielke ◽

Yang Liao ◽

Ella Bridie Clemens ◽

Matthew A. Firth ◽

Brigette Duckworth ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cell Fate ◽

Cd8 T Cells ◽

Cd8 T Cell ◽

T Cell Subsets ◽

Double Positive ◽

Cell Fate Decisions ◽

Healthy Humans ◽

Tc17 Cells

Interleukin (IL)-17–producing CD8+ T (Tc17) cells have emerged as key players in host-microbiota interactions, infection, and cancer. The factors that drive their development, in contrast to interferon (IFN)-γ–producing effector CD8+ T cells, are not clear. Here we demonstrate that the transcription factor TCF-1 (Tcf7) regulates CD8+ T cell fate decisions in double-positive (DP) thymocytes through the sequential suppression of MAF and RORγt, in parallel with TCF-1–driven modulation of chromatin state. Ablation of TCF-1 resulted in enhanced Tc17 cell development and exposed a gene set signature to drive tissue repair and lipid metabolism, which was distinct from other CD8+ T cell subsets. IL-17–producing CD8+ T cells isolated from healthy humans were also distinct from CD8+IL-17− T cells and enriched in pathways driven by MAF and RORγt. Overall, our study reveals how TCF-1 exerts central control of T cell differentiation in the thymus by normally repressing Tc17 differentiation and promoting an effector fate outcome.

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The Role of Bone Marrow T Cells in Regulating Hematopoietic Stem Cell Function.

Blood ◽

10.1182/blood.v120.21.2349.2349 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2349-2349

Author(s):

Claudia Brandao ◽

Alexander M. de Bruin ◽

Martijn A. Nolte

Keyword(s):

Bone Marrow ◽

T Cells ◽

Immune System ◽

T Cell ◽

Cd8 T Cells ◽

Feedback Mechanism ◽

T Cell Subsets ◽

Effector Memory ◽

Self Renewal ◽

Hematopoietic Stem

Abstract Abstract 2349 After immune activation, effector/memory T cells, including virus-specific CD8 T cells, are known to migrate to the bone marrow (BM), where they can be maintained by the production of IL-15 by the stroma; however, it is not yet known whether these T cells also have a function at this site. Since depletion of T cells from allogenic BM grafts compromises HSC engraftment, we hypothesize that T cells can directly influence the balance between differentiation and self-renewal of hematopoietic stem cells (HSCs). To test the ability of T cells to affect hematopoiesis, we performed co-cultures of HSCs and T cells isolated from murine BM. We found that T cells localized in the BM are able to enhance HSC differentiation as well as their self-renewal capacity. This feature is specific for BM central memory (CM) CD8 T cells, since other T cell subsets are not able to affect HSCs to the same extent. Moreover, depletion of CM CD8 T cells from the total BM T cell pool abrogates the impact on HSC differentiation and self-renewal, indicating that this particular T cell population is both sufficient and required for the observed effects. BM CM CD8 T cells do not affect quiescence of HSCs, but do enhance their proliferative capacity, and we found that supernatant from CM CD8 T cells is sufficient for this effect. Interestingly, competitive transplantation assays showed that HSCs cultured with CM CD8 T cells-derived supernatant contribute much better to leukocyte formation than medium-treated HSCs. This effect is seen in both the myeloid and lymphoid compartment, indicating that CM CD8 T cells are able to release soluble factors that support and enhance the multilineage reconstitution capacity of HSCs. Functional studies with blocking antibodies or knock-out mice showed that the supernatant-mediated effect is not caused by the hematopoietic cytokines IL3, IL6, IL21, GM-CSF, RANTES, TNFα or IFNγ. Preliminary data indicate that this feedback mechanism of the immune system on the hematopoietic process in the bone marrow is also present in the human situation, since autologous BM T cells increase the numbers of human HSCs, as well as their differentiation capacity. Overall, these findings demonstrate that T cells have an important function in the BM and that especially CD8 TCM cells can directly influence HSC homeostasis. We postulate that this feedback mechanism of the immune system on the hematopoietic process in the BM is particularly relevant during viral infection, as the efficient migration of virus-specific CD8 T cells to the BM could well benefit the replenishment of the HSC/progenitor cell compartment and restoration of blood cell numbers that got lost upon infection. Disclosures: No relevant conflicts of interest to declare.

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Prolonged Thrombocytopenia After Allogeneic Hematopoietic Stem Cell Transplantation (allo-HSCT) and Its Association with an Increase in CD8+ CX3CR1+ Cells in Bone Marrow.

Blood ◽

10.1182/blood.v120.21.3077.3077 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3077-3077

Author(s):

Xiao-hui Zhang ◽

Guo-xiang Wang ◽

Yan-rong Liu ◽

Lan-Ping Xu ◽

Kai-Yan Liu ◽

...

Keyword(s):

Bone Marrow ◽

T Cells ◽

T Cell ◽

Cd8 T Cells ◽

Surface Expression ◽

T Cell Subsets ◽

Control Group ◽

Hematopoietic Stem ◽

Cell Counts

Abstract Abstract 3077 Background: Since prolonged thrombocytopenia (PT) is an independent risk factor for poor clinical outcome after allogeneic hematopoietic stem cell transplantation (allo-HSCT), the underlying mechanisms need to be understood in order to develop selective treatments. Previous studies1–4 have suggested that abnormalities in B cells may play a role in the pathogenesis of PT. However, abnormalities in B cells alone do not fully explain the complete pathogenic mechanisms of PT. Our previous studies5 showed that the frequency of megakaryocytes with a ploidy value ≤ 8N was significantly increased in patients who developed PT after allo-HSCT compared to the control group. Mechanisms concerning the megakaryocyte hypoplasia in PT after allo-HSCT are not well understood. Design and Methods: PT was defined as a platelet count ≤80 × 109/L for more than 3 months after HSCT, recovery of all other cell counts, and no apparent cause for thrombocytopenia, such as aGVHD, disease recurrence, CMV infection, or antiviral drug treatment at three months post-HSCT when all other blood cell counts had return to normal.5 We analyzed T cell subsets in bone marrow (BM) and peripheral blood (PB) from allo-HSCT recipients with and without PT (n = 23 and 17, respectively) and investigated the expression characteristics of homing receptors CX3CR1, CXCR4 and VLA-4 by flow cytometry. Futhermore, Mononuclear cells (MNCs) from PT patients and controls were cultured with and without autologous CD8+ T cells in vitro, and clarify the effect of activated CD8+ T cells on the ploidy and apoptosis of megakaryocytes in the bone marrow. Results: The results demonstrated that the percentage of CD3+ T cells in the BM was significantly higher in PT patients than the experimental controls (76.00 ± 13.04% and 57.49 ± 9.11%, respectively, P < 0.001), whereas this difference was not significant for the PB (71.01 ± 11.49% and 70.49 ± 12.89%, respectively, P = 0.911). While, some T cell subsets in the BM and PB from allo-HSCT recipients with PT were not significantly different from that of the experimental control group, such as CD8+ T cells, CD4+ T cells, CD4+ CD25bright T cells (regulatory T cells), CD44hi CD62Llo CD8+ T cells and naive T cells (CD11a+ CD45RA+). Furthermore, the surface expression of homing receptor CX3CR1 on BM T cells (64.16 ± 14.07% and 37.45 ± 19.66%, respectively, P < 0.001) and CD8+ T cells (56.25 ± 14.54% and 35.16 ± 20.81%, respectively, P = 0.036), but not in blood, were significantly increased in PT patients compared to controls. For these two groups of patients, the surface expression of CXCR4 and VLA-4 on T cells and CD8+ T cells from both BM and PB did not show significant differences. Through the study in vitro, we found that the activated CD8+ T cells in bone marrow of patients with PT might suppress apoptosis (MNC group and Co-culture group: 18.02 ± 3.60% and 13.39 ± 4.22%, P < 0.05, respectively) and Fas expression (MNC group and Co-culture group: 21.10 ± 3.93 and 15.10 ± 2.33, P <0.05, respectively) of megakaryocyte. In addition, megakaryocyte with a ploidy value ≤ 8N (MNC group: 40.03 ± 6.42% and 24.54 ± 4.31%, respectively, P < 0.05) was significantly increased in patients with PT compared to the control group. Conclusions: In conclusion, an increased surface expression of CX3CR1 on T cells may mediate the recruitment of CD8+ T cells into the bone marrow in patients with PT who received an allo-HSCT. Moreover, CD8+CX3CR1+ T cells, which can have significantly increased numbers in bone marrow of patients with PT, likely caused a reduction in the megakaryocyte ploidy, and suppressed megakaryocyte apoptosis via CD8+ T cell-mediated cytotoxic effect, possibly leading to impaired platelet production. Therefore, treatment targeting CX3CR1 should be considered as a reasonable therapeutic strategy for PT following allo-HSCT. Disclosures: No relevant conflicts of interest to declare.

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Anti-Thymocyte Globulin (ATG) Differentially Depletes naïve and Memory T Cells and Permits Memory-Type Regulatory T Cells

Blood ◽

10.1182/blood.v120.21.4670.4670 ◽

2012 ◽

Vol 120 (21) ◽

pp. 4670-4670

Author(s):

Chang-Qing Xia ◽

Anna Chernatynskaya ◽

Clive Wasserfall ◽

Benjamin Looney ◽

Suigui Wan ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Regulatory T Cells ◽

Cd8 T Cells ◽

Peripheral Blood ◽

Memory T Cells ◽

Conflicts Of Interest ◽

T Cell Subsets ◽

Hematopoietic Stem

Abstract Abstract 4670 Anti-thymocyte globulin (ATG) has been used in clinic for the treatment of allograft rejection and autoimmune diseases. However, its mechanism of action is not fully understood. To our knowledge, how ATG therapy affects naïve and memory T cells has not been well investigated. In this study, we have employed nonobese diabetic mouse model to investigate how administration of anti-thymocyte globulin (ATG) affects memory and naïve T cells as well as CD4+CD25+Foxp3+ regulatory T cells in peripheral blood and lymphoid organs; We also investigate how ATG therapy affects antigen-experienced T cells. Kinetic studies of peripheral blood CD4+ and CD8+ T cells post-ATG therapy shows that both populations decline to their lowest levels at day 3, while CD4+ T cells return to normal levels more rapidly than CD8+ T cells. We find that ATG therapy fails to eliminate antigen-primed T cells, which is consistent with the results that ATG therapy preferentially depletes naïve T cells relative to memory T cells. CD4+ T cell responses post-ATG therapy skew to T helper type 2 (Th2) and IL-10-producing T regulatory type 1 (Tr1) cells. Intriguingly, Foxp3+ regulatory T cells (Tregs) are less sensitive to ATG depletion and remain at higher levels following in vivo recovery compared to controls. Of note, the frequency of Foxp3+ Tregs with memory-like immunophenotype is significantly increased in ATG-treated animals, which might play an important role in controlling effector T cells post ATG therapy. In summary, ATG therapy may modulate antigen-specific immune responses through modulation of naïve and memory T cell pools and more importantly through driving T cell subsets with regulatory activities. This study provides important data for guiding ATG therapy in allogenieic hematopoietic stem cell transplantation and other immune-mediated disorders. Disclosures: No relevant conflicts of interest to declare.

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Specific expression of the human CD4 gene in mature CD4+ CD8- and immature CD4+ CD8+ T cells and in macrophages of transgenic mice.

Molecular and Cellular Biology ◽

10.1128/mcb.14.2.1084 ◽

1994 ◽

Vol 14 (2) ◽

pp. 1084-1094 ◽

Cited By ~ 42

Author(s):

Z Hanna ◽

C Simard ◽

A Laperrière ◽

P Jolicoeur

Keyword(s):

T Cells ◽

T Cell ◽

Transgenic Mice ◽

Cd8 T Cells ◽

Transcription Initiation ◽

Critical Role ◽

Regulatory Elements ◽

T Cell Subsets ◽

Double Positive ◽

Specific Expression

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T Cell subsets mediating lethal graft versus host disease: Demonstration that synergy between CD4+ and CD8+ T cells is the predominant mechanism in low responder rat strains

Cellular Immunology ◽

10.1016/0008-8749(89)90097-x ◽

1989 ◽

Vol 122 (2) ◽

pp. 517-523 ◽

Cited By ~ 4

Author(s):

Nicholas W. Pearce ◽

Bruce M. Hall ◽

Susan E. Dorsch

Keyword(s):

T Cells ◽

T Cell ◽

Graft Versus Host Disease ◽

Cd8 T Cells ◽

T Cell Subsets ◽

Rat Strains ◽

Host Disease ◽

Graft Versus Host ◽

Low Responder

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Long-Term Persistence of Functionally Altered GPI-Anchor Negative T-Cell Subsets After Alemtuzumab-Based T-Cell Depleted Hematopoietic Stem Cell Transplantation.

Blood ◽

10.1182/blood.v114.22.2438.2438 ◽

2009 ◽

Vol 114 (22) ◽

pp. 2438-2438

Author(s):

Eva M Wagner ◽

Aline N Lay ◽

Timo Schmitt ◽

Julia Hemmerling ◽

Diana Wolff ◽

...

Keyword(s):

T Cells ◽

Stem Cell ◽

T Cell ◽

Hematopoietic Stem Cell Transplantation ◽

Cd8 T Cells ◽

T Cell Subsets ◽

Gpi Anchor ◽

Ifn Gamma ◽

Hematopoietic Stem

Abstract Abstract 2438 Poster Board II-415 The anti CD52 antibody alemtuzumab is frequently used for in vivo T cell depletion (TCD) in the context of allogeneic hematopoietic stem cell transplantation (HSCT). We have recently demonstrated the persistence of CD52-negative T-cell subsets in patients after HSCT following alemtuzumab-mediated TCD (Meyer, Wagner et al., Bone Marrow Transplantation 2009). The loss of CD52 among lymphocytes was exclusively related to T cells and was more prominent in CD4 compared to CD8 T cells. CD8-depleted donor-lymphocyte infusions (DLI) increased the percentage of CD52-positive CD4 T cells. In patients who did not receive DLI, CD52-negative T cells were detected in significant proportions of up to 40% found even more than 3 years after transplantation. We therefore investigated the regulation as well as the functional consequences of a loss of CD52-expression in T cells of our patients. Peripheral blood T cells of patients with CD52-negative T cells after more than 12 months post allogeneic HSCT following TCD with high-dose alemtuzumab (100 mg) were sorted according to their expression of CD52. RT-PCR showed no difference in CD52 mRNA expression of CD52-positive compared to negative T cells. Since transcriptional regulation was therefore unlikely and CD52 is a glycosylphosphatidylinositol (GPI)-anchored protein, we stained for the presence of further GPI-anchored molecules such as CD55 and CD59 on peripheral blood lymphocytes of our patients. We found that the CD52-negative T cells had also lost expression of CD55 and CD59, whereas CD52-positive cells remained positive for these antigens. We then directly labeled the GPI-anchors using FLAER (fluorescent aerolysin) and thereby confirmed that the loss of CD52 was correlated with a reduced density of the GPI-anchors in the cell-membrane. However, our patients did not exhibit clinical signs of paroxysmal nocturnal hemoglobinuria (PNH), which is in line with the finding that the loss of GPI-anchors was only related to T cells. With the aim to characterize the functional impact of the reduced GPI-anchor density on T cells, we separated CD52-negative from CD52-positive T cells by flow cytometry. The subpopulations were expanded in vitro using low-dose IL2, OKT3, and allogeneic feeder-cells. CD52 expression remained unaltered in CD52-negative as well as CD52-positive cultures for more than 6 weeks. In contrast, when purified T cells of healthy donors were treated with alemtuzumab in vitro (10 μg/mL, 4 h), we only observed a transient down-regulation of the antigen. The growth-kinetics of the non-specifically stimulated T cell cultures did not differ between the CD52-positive and the negative cultures. Yet, when we expanded T cells of a cytomegalovirus (CMV)-positive patient, transplanted from a CMV-positive donor, by subsequent stimulation with overlapping peptides of CMV-pp65, only the proliferation of CD52-positive T cells increased after the addition of peptides. We furthermore applied CD52-positive as well as CD52-negative CD4 and CD8 T cells derived from the antigen-independent culture of this patient in an IFN-gamma ELISPOT assay with autologous dendritic cells (DC) loaded with overlapping peptides of CMV-pp65 and IE1. CMV-specific IFN-gamma spot-production was only evident in the CD52-positive populations. We also conducted IFN-gamma secretion-assays on ex vivo T cells stimulated with autologous DC loaded with CMV-peptides and found a reduced antigen-specific IFN-gamma production in CD52-negative CD4 and CD8 T cells. In addition, we analyzed IFN-gamma secretion of T cells following allogeneic stimulation with DC of a healthy individual and again detected lower levels of IFN-gamma production by CD52-negative compared to CD52-positive T cells. In summary, we demonstrated that the permanent loss of CD52 in a proportion of reconstituting T cells after alemtzumab-based TCD is associated with a loss of GPI-anchors in the cellular membrane. Our data suggest that this loss correlates with reduced T-cell effector-functions in response to antigen-specific stimulation. In addition to a better understanding of the role of alemtuzumab-mediated TCD on T cell reconstitution, further comparison of functional responses in different T-cell subsets in association with the presence or absence of GPI-anchors might help to explore the impact of GPI-anchors and GPI-anchored molecules in this context. Disclosures: No relevant conflicts of interest to declare.

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CCR2 is required for CD8-induced graft-versus-host disease

Blood ◽

10.1182/blood-2005-05-1860 ◽

2005 ◽

Vol 106 (9) ◽

pp. 3322-3330 ◽

Cited By ~ 68

Author(s):

Theis H. Terwey ◽

Theo D. Kim ◽

Adam A. Kochman ◽

Vanessa M. Hubbard ◽

Sydney Lu ◽

...

Keyword(s):

T Cells ◽

Cell Migration ◽

T Cell ◽

Graft Versus Host Disease ◽

Cd8 T Cells ◽

Cd8 T Cell ◽

Hematopoietic Stem ◽

Host Disease ◽

Graft Versus Host ◽

T Cell Migration

AbstractGraft-versus-host disease (GVHD) is a major complication of allogeneic hematopoietic stem cell transplantation (HSCT). Migration of donor-derived T cells into GVHD target organs plays a critical role in the development of GVHD and chemokines and their receptors are important molecules involved in this process. Here, we demonstrate in murine bone marrow transplantation models that the expression of the inflammatory CC chemokine receptor 2 (CCR2) on donor-derived CD8+ T cells is relevant for the control of CD8+ T-cell migration and development of GVHD. Recipients of CCR2-deficient (CCR2-/-) CD8+ T cells developed less damage of gut and liver than recipients of wild-type CD8+ T cells, which correlated with a reduction in overall GVHD morbidity and mortality. Assessment of donor CD8+ T-cell target organ infiltration revealed that CCR2-/- CD8+ T cells have an intrinsic migratory defect to the gut and liver. Other causes for the reduction in GVHD could be excluded, as alloreactive proliferation, activation, IFN-γ production and cytotoxicity of CCR2-/- CD8+ T cells were intact. Interestingly, the graft-versus-tumor effect mediated by CCR2-/- CD8+ T cells was preserved, which suggests that interference with T-cell migration by blockade of CCR2 signaling can separate GVHD from GVT activity.

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