scholarly journals Requirement for CD8+ T cells in the development of airway hyperresponsiveness in a marine model of airway sensitization.

1996 ◽  
Vol 183 (4) ◽  
pp. 1719-1729 ◽  
Author(s):  
E Hamelmann ◽  
A Oshiba ◽  
J Paluh ◽  
K Bradley ◽  
J Loader ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Airway Hyperresponsiveness ◽  
Critical Role ◽  
Allergic Sensitization ◽  
Lung Parenchyma ◽  
Airway Responsiveness ◽  
Eosinophil Infiltration ◽  
Lymphoid Tissues

To study the role of CD8+ T cells in allergic sensitization, we examined the effects of in vivo depletion of CD8+ T cells prior to sensitization on IgE production, immediate type cutaneous hypersensitivity and development of altered airway responsiveness. BALB/c mice were thymectomized and treated with anti-CD8 antibody resulting in depletion of CD8+ T cells (<1%) in spleen and lymphoid tissues. In these mice, sensitization to ovalbumin (OVA) via the airways still resulted in IgE anti-OVA responses and immediate cutaneous reactions to OVA, but the animals were unable to develop airway hyperresponsiveness, eosinophil infiltration of the lung parenchyma, or IL-5 production in the local lymph nodes of the airway. Transfer of CD8+ T cells from naive animals during sensitization (on day 8 of the 10-d protocol) fully restored the ability to develop airway hyperresponsiveness and this was accompanied by IL-5 production and eosinophil accumulation in the lung. These data indicate a critical role for CD8+ T cells in the production of IL-5 and the development of altered airway responsiveness after antigen sensitization through the airways.

scholarly journals Preferential Small Intestine Homing and Persistence of CD8 T Cells in Rhesus Macaques Achieved by Molecularly Engineered Expression of CCR9 and Reduced Ex Vivo Manipulation

2019 ◽  
Vol 93 (21) ◽  
Author(s):  
Matthew T. Trivett ◽  
James D. Burke ◽  
Claire Deleage ◽  
Lori V. Coren ◽  
Brenna J. Hill ◽  
...  
Keyword(s):  
T Cells ◽  
Small Intestine ◽  
T Cell ◽  
Rhesus Macaque ◽  
Cd8 T Cells ◽  
Ex Vivo ◽  
Rhesus Macaques ◽  
Lymphoid Tissues ◽  
Aids Virus

ABSTRACT Adoptive cell transfer (ACT) is a powerful experimental approach to directly study T-cell-mediated immunity in vivo. In the rhesus macaque AIDS virus model, infusing simian immunodeficiency virus (SIV)-infected animals with CD8 T cells engineered to express anti-SIV T-cell receptor specificities enables direct experimentation to better understand antiviral T-cell immunity in vivo. Limiting factors in ACT experiments include suboptimal trafficking to, and poor persistence in, the secondary lymphoid tissues targeted by AIDS viruses. Previously, we redirected CD8 T cells to B-cell follicles by ectopic expression of the CXCR5 homing protein. Here, we modify peripheral blood mononuclear cell (PBMC)-derived CD8 T cells to express the CCR9 chemokine receptor, which induces preferential homing of the engineered cells to the small intestine, a site of intense early AIDS virus replication and pathology in rhesus macaques. Additionally, we increase in vivo persistence and overall systemic distribution of infused CD8 T cells, especially in secondary lymphoid tissues, by minimizing ex vivo culture/manipulation, thereby avoiding the loss of CD28+/CD95+ central memory T cells by differentiation in culture. These proof-of-principle results establish the feasibility of preferentially localizing PBMC-derived CD8 T cells to the small intestine and enables the direct experimental ACT-based assessment of the potential role of the quality and timing of effective antiviral CD8 T-cell responses to inhibit viral infection and subsequent replication in small intestine CD4 T cells. More broadly, these results support the engineered expression of homing proteins to direct CD8 T cells to target tissues as a means for both experimental and potential therapeutic advances in T-cell immunotherapies, including cancer. IMPORTANCE Adoptive cell transfer (ACT) of T cells engineered with antigen-specific effector properties can deliver targeted immune responses against malignancies and infectious diseases. Current T-cell-based therapeutic ACT relies on circulatory distribution to deliver engineered T cells to their targets, an approach which has proven effective for some leukemias but provided only limited efficacy against solid tumors. Here, engineered expression of the CCR9 homing receptor redirected CD8 T cells to the small intestine in rhesus macaque ACT experiments. Targeted homing of engineered T-cell immunotherapies holds promise to increase the effectiveness of adoptively transferred cells in both experimental and clinical settings.

scholarly journals Plasmacytoid dendritic cells cross-prime naive CD8 T cells by transferring antigen to conventional dendritic cells through exosomes

2020 ◽  
Vol 117 (38) ◽  
pp. 23730-23741 ◽  
Author(s):  
Chunmei Fu ◽  
Peng Peng ◽  
Jakob Loschko ◽  
Li Feng ◽  
Phuong Pham ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Cd8 T Cells ◽  
Critical Role ◽  
Plasmacytoid Dendritic Cells ◽  
Viral Immunity ◽  
Cell Immunity ◽  
Antigen Transfer

Although plasmacytoid dendritic cells (pDCs) have been shown to play a critical role in generating viral immunity and promoting tolerance to suppress antitumor immunity, whether and how pDCs cross-prime CD8 T cells in vivo remain controversial. Using a pDC-targeted vaccine model to deliver antigens specifically to pDCs, we have demonstrated that pDC-targeted vaccination led to strong cross-priming and durable CD8 T cell immunity. Surprisingly, cross-presenting pDCs required conventional DCs (cDCs) to achieve cross-priming in vivo by transferring antigens to cDCs. Taking advantage of an in vitro system where only pDCs had access to antigens, we further demonstrated that cross-presenting pDCs were unable to efficiently prime CD8 T cells by themselves, but conferred antigen-naive cDCs the capability of cross-priming CD8 T cells by transferring antigens to cDCs. Although both cDC1s and cDC2s exhibited similar efficiency in acquiring antigens from pDCs, cDC1s but not cDC2s were required for cross-priming upon pDC-targeted vaccination, suggesting that cDC1s played a critical role in pDC-mediated cross-priming independent of their function in antigen presentation. Antigen transfer from pDCs to cDCs was mediated by previously unreported pDC-derived exosomes (pDCexos), that were also produced by pDCs under various conditions. Importantly, all these pDCexos primed naive antigen-specific CD8 T cells only in the presence of bystander cDCs, similarly to cross-presenting pDCs, thus identifying pDCexo-mediated antigen transfer to cDCs as a mechanism for pDCs to achieve cross-priming. In summary, our data suggest that pDCs employ a unique mechanism of pDCexo-mediated antigen transfer to cDCs for cross-priming.

scholarly journals Identification of a distant T-bet enhancer responsive to IL-12/Stat4 and IFNγ/Stat1 signals

Blood ◽  
2007 ◽  
Vol 110 (7) ◽  
pp. 2494-2500 ◽  
Author(s):  
Yu Yang ◽  
Jordi C. Ochando ◽  
Jonathan S. Bromberg ◽  
Yaozhong Ding
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
Reporter Gene ◽  
Cd8 T Cells ◽  
Critical Role ◽  
Luciferase Reporter ◽  
Reporter Assay ◽  
Wild Type ◽  
Th1 Polarization

T-bet plays a critical role in controlling IFNγ expression, Th1 polarization, and CD8 cytolytic development. Its regulation has been demonstrated to be mostly IFNγ/Stat1 dependent while IL-12/Stat4 independent. Here we show that IL-12/Stat4 binds to a distant highly conserved STAT-responsive T-bet enhancer, and induces IFNγ/Stat1-independent T-bet expression in CD8 T cells. Luciferase reporter assay showed that both Stat4 and Stat1 activate reporter gene expression from constructs containing a wild-type but not mutated T-bet enhancer. Studies in virus-infected mice demonstrated that the IL-12/Stat4/T-bet cascade operates in vivo and regulates IFNγ in CD8 T cells. Together, we provide a novel mechanism for T-bet regulation, and suggest that IL-12/Stat4/T-bet play an important role in CD8 effector responses.

scholarly journals Selective Generation of Gut Tropic T Cells in Gut-associated Lymphoid Tissue (GALT)

2003 ◽  
Vol 198 (6) ◽  
pp. 963-969 ◽  
Author(s):  
Bengt Johansson-Lindbom ◽  
Marcus Svensson ◽  
Marc-André Wurbel ◽  
Bernard Malissen ◽  
Gabriel Márquez ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Intestinal Epithelium ◽  
Critical Role ◽  
Lymphoid Tissues ◽  
Transfer Model ◽  
Small Intestinal Epithelium ◽  
Selective Generation ◽  
Small Intestinal

In the current study, we address the underlying mechanism for the selective generation of gut-homing T cells in the gut-associated lymphoid tissues (GALT). We demonstrate that DCs in the GALT are unique in their capacity to establish T cell gut tropism but in vivo only confer this property to T cells in the presence of DC maturational stimuli, including toll-like receptor-dependent and -independent adjuvants. Thus, DCs from mesenteric LNs (MLNs), but not from spleen, supported expression of the chemokine receptor CCR9 and integrin α4β7 by activated CD8+ T cells. While DCs were also required for an efficient down-regulation of CD62L, this function was not restricted to MLN DCs. In an adoptive CD8+ T cell transfer model, antigen-specific T cells entering the small intestinal epithelium were homogeneously CCR9+α4β7+CD62Llow, and this phenotype was only generated in GALT and in the presence of adjuvant. Consistent with the CCR9+ phenotype of the gut-homing T cells, CCR9 was found to play a critical role in the localization of T cells to the small intestinal epithelium. Together, these results demonstrate that GALT DCs and T cell expression of CCR9 play critical and integrated roles during T cell homing to the gut.

Vaccination with ΔCD40L or Flagellin Gene-Modified T Cells Activates Dendritic Cells In Vivo and Induces a Potent Anti-Tumor Immune Response

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1909-1909
Author(s):  
Adham S Bear ◽  
Meghan M Turnis ◽  
Xiao-Tong Song ◽  
Russell Cruz ◽  
An Lu ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Dendritic Cells ◽  
Lymph Nodes ◽  
Tumor Cells ◽  
Cd8 T Cells ◽  
Lymphoid Tissues ◽  
Protective Effects ◽  
Facs Analysis

Abstract Abstract 1909 Introduction: Cancer vaccines have shown promise in small animal models of cancer, but have thus far been disappointing in clinical settings. Successful induction of a systemic and long-term anti-tumor immune response following vaccination is dependent on delivery of tumor-associated antigens to lymphoid tissues, in combination with the activation of professional antigen presenting cells (APCs). Here we describe a novel live T cell vaccine (TCV) that delivers antigenic peptides to secondary lymph nodes while simultaneously activating endogenous dendritic cells (DCs) through transgenic expression of CD40L or bacterial flagellin (fliC). Methods: To generate TCVs, murine splenocytes were isolated from wild-type type C57BL/6 mice. Following activation with anti-CD3/anti-CD28 microbeads, splenocytes were transduced with pRV2011-luciferase-IRES-Thy1.1, pRV2011-CD40L-IRES-Thy1.1 or pRV2011-fliC-IRES-Thy1.1 retrovirus. Analysis of TCV migration to lymphoid organs was performed by bioluminescence imaging for firefly luciferase. Following transduction with CD40L and fliC molecules, TCVs were measured for transduction efficiency (Thy1.1) and transgene expression using FACS analysis of CD40L or by Western blot, respectively. TCVs were subsequently pulsed with MHC class I-restricted epitopes for ovalbumin257-264 (SIINFEKL) or Trp2180-188 (SVYDFFVWL) peptides and injected intravenously at a dose of 1×107 TCVs per vaccination. To test the protective effects of TCVs, C57BL/6 mice were immunized at days 0 and 14 and then challenged with either 5×105 B16-OVA (for TCV-SIIN) or parental B16.F10 (for TCV-SVYD) melanoma tumor cells. To examine the ability of TCVs to eliminate established tumors, mice received B16-OVA or B16.F10 tumor cells followed by vaccination with TCVs on days 3, 9 and 15. Immunological studies were performed on a subset of mice (n=5 per group) to analyze induction of tumor-specific T cells using tetramer and IFN-g ELIspot assays. In vivo activation of lymph node DCs was performed by FACS analysis for CD11c+ DC co-expressing CD86 and I-A/I-E mouse MHC class II antibodies. Results: Following activation, TCVs were efficiently transduced with retrovirus (>85% CD40L) or expressed high levels of fliC. Bioluminescent imaging showed that luciferase-expressing TCVs rapidly migrated to lymphoid organs including the spleen and cervical and inguinal lymph nodes demonstrating the capacity of TCVs to co-localize with professional APCs. Importantly, irradiation (30 Gy) of TCVs completely abrogated migration and persistence highlighting the requirement for live TCVs. Next we examined whether TCV-CD40L or TCV-fliC could induce a protective immune response against B16 tumors. Administration of TCV-fliC-SIIN (OVA) and TCV-CD40L-SIIN primed peptide-specific CD8+ T cells, and led to decreased tumor growth and increased survival in mice subsequently challenged with B16-Ova (p<0.05). This response corresponded with a statistically significant (p<.05) increase in SIIN-specific CD8+ T cells as measured by tetramer FACS analysis and IFN-g ELIspot assays. Vaccination of mice with established tumors showed similar tumor suppression with both TCV designs (p<05). As OVA is a xenogenic antigen, we next examined whether TCVs pulsed with Trp2 peptide (SVYD) could induce similar protective effects. While vaccination with SVYD-pulsed T cells alone (no gene modification) did not inhibit tumor growth, expression of CD40L or fliC by TCV pulsed with Trp2 peptide suppressed B16.F10 tumor proliferation and increased survival in mice with pre-established tumors (p<.05). As found in the B16.OVA experiments, immunological protection correlated with a dramatic increase in SVYD-specific CD8+ T cells in the spleen, tumor draining lymph nodes and tumor. Conclusions: The efficient delivery of tumor-associated antigens to lymphoid tissues by TCVs overcomes a major limitation of alternative vaccine strategies. Vaccination with peptide-pulsed TCVs primes antigen-specific T cell responses with anti-tumor capability, and endogenous DC maturation leads to the inhibition of established B16-Ova and B16-F10 tumors. This illustrates the role of endogenous DC as mediators of the vaccine response and demonstrates the effectiveness of using TCVs to deliver antigen in the context of DC activating molecules. Disclosures: No relevant conflicts of interest to declare.

scholarly journals A critical role for direct TLR2-MyD88 signaling in CD8 T-cell clonal expansion and memory formation following vaccinia viral infection

Blood ◽  
2009 ◽  
Vol 113 (10) ◽  
pp. 2256-2264 ◽  
Author(s):  
Michael Quigley ◽  
Jennifer Martinez ◽  
Xiaopei Huang ◽  
Yiping Yang
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Critical Role ◽  
Clonal Expansion ◽  
Cd8 T Cell ◽  
Cell Responses ◽  
Pathway Activation ◽  
Myd88 Signaling

Abstract Recent advances have suggested a crucial role of the innate immunity in shaping adaptive immune responses. How activation of innate immunity promotes adaptive T-cell responses to pathogens in vivo is not fully understood. It has been thought that Toll-like receptor (TLR)–mediated control of adaptive T-cell responses is mainly achieved by the engagement of TLRs on antigen-presenting cells to promote their maturation and function. In this study, we showed that direct TLR2–myeloid differentiating factor 88 (MyD88) signaling in CD8 T cells was also required for their efficient clonal expansion by promoting the survival of activated T cells on vaccinia viral infection in vivo. Effector CD8 T cells that lacked direct TLR2-MyD88 signaling did not survive the contraction phase to differentiate into long-lived memory cells. Furthermore, we observed that direct TLR2 ligation on CD8 T cells promoted CD8 T-cell proliferation and survival in vitro in a manner dependent on the phosphatidylinositol 3-kinase (PI3K)–Akt pathway activation and that activation of Akt controlled memory cell formation in vivo. These results identify a critical role for intrinsic TLR2-MyD88 signaling and PI3K-Akt pathway activation in CD8 T-cell clonal expansion and memory formation in vivo and could lead to the development of new vaccine approaches.

scholarly journals HIV-specific CD8+ T cells from HIV+ individuals receiving HAART can be expanded ex vivo to augment systemic and mucosal immunity in vivo

Blood ◽  
2011 ◽  
Vol 117 (20) ◽  
pp. 5391-5402 ◽  
Author(s):  
Aude G. Chapuis ◽  
Corey Casper ◽  
Steve Kuntz ◽  
Jia Zhu ◽  
Annelie Tjernlund ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Highly Active Antiretroviral Therapy ◽  
Ex Vivo ◽  
Rectal Mucosa ◽  
Cd8 T Cell ◽  
Lymphoid Tissues ◽  
Therapeutic Vaccines

AbstractMost HIV+ individuals require lifelong highly active antiretroviral therapy (HAART) to suppress HIV replication, but fail to eliminate the virus in part because of residual replication in gut-associated lymphoid tissues (GALT). Naturally elicited HIV-specific CD8+ T cells generated in the acute and chronic infectious phases exhibit antiviral activity, but decrease in number after HAART. Therapeutic vaccines represent a potential strategy to expand cellular responses, although previous efforts have been largely unsuccessful, conceivably because of a lack of responding HIV-specific central-memory CD8+ T cells (Tcm). To determine whether patients receiving HAART possess CD8+ T cells with Tcm qualities that are amenable to augmentation, HIV-specific CD8+ T-cell clones were derived from HIV-reactive CD28+CD8+ T-cell lines isolated from 7 HIV+ HAART-treated patients, expanded ex vivo, and reinfused into their autologous host. Tracking of the cells in vivo revealed that clones could persist for ≥ 84 days, maintain expression and/or re-express CD28, up-regulate CD62L, secrete IL-2, proliferate on cognate Ag encounter and localize to the rectal mucosa. These results suggest some infused cells exhibited phenotypic and functional characteristics shared with Tcm in vivo, and imply that more effective therapeutic vaccination strategies targeting CD8+ Tcm in patients on HAART might provide hosts with expanded, long-lasting immune responses not only systemically but also in GALT. This study is registered at www.clinicaltrials.gov as NCT00110578.

scholarly journals Virus-specific CD8+ T cells accumulate near sensory nerve endings in genital skin during subclinical HSV-2 reactivation

2007 ◽  
Vol 204 (3) ◽  
pp. 595-603 ◽  
Author(s):  
Jia Zhu ◽  
David M. Koelle ◽  
Jianhong Cao ◽  
Julio Vazquez ◽  
Meei Li Huang ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Critical Role ◽  
Immune Surveillance ◽  
Sensory Nerve ◽  
Nerve Endings ◽  
Viral Reactivation ◽  
Skin Biopsies ◽  
Simplex Virus

Cytotoxic CD8+ T cells play a critical role in controlling herpes simplex virus (HSV) infection and reactivation. However, little is known about the spatiotemporal dynamics of CD8+ T cells during HSV lesion evolution or about their involvement in immune surveillance after lesion resolution. Using quantum dot–conjugated peptide–major histocompatibility complex multimers, we investigated the in vivo localization of HSV-2–specific CD8+ T cells in sequential biopsies of human genital skin during acute, resolving, and healed stages of HSV-2 reactivation. Our studies revealed that functionally active CD8+ T cells selectively infiltrated to the site of viral reactivation. After lesion healing in concert with complete reepithelialization and loss of HSV DNA from skin biopsies, HSV-2–specific CD8+ T cells persisted for more than two months at the dermal–epidermal junction, adjacent to peripheral nerve endings. In two out of the six sequentially studied individuals, HSV-2 DNA reappeared in clinically and histologically normal–appearing skin. Detection of viral DNA was accompanied by increased numbers of both HSV-specific and total CD8+ T cells in the dermis. These findings indicate that the frequency and clinical course of HSV-2 reactivation in humans is influenced by virus-specific CD8+ T cells that persist in peripheral mucosa and genital skin after resolution of herpes lesions.

A Critical Role of MyD88 Signaling in Donor T Cells for Graft-Versus-Host Disease (GVHD) and Graft-Versus-Leukemia Effect (GVL) After Experimental Allogeneic Hematopoietic Stem Cell Transplantation (allo-HSCT)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1893-1893
Author(s):  
Ji-Young Lim ◽  
Dae-Chul Jeong ◽  
Hyewon Youn ◽  
Eun-Young Choi ◽  
Chang-Ki Min
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Critical Role ◽  
Hematopoietic Stem ◽  
Donor T Cells ◽  
Myd88 Signaling

Abstract Abstract 1893 The therapeutic potential of allogeneic hematopoietic stem cell transplantation (allo-HSCT) relies on the graft-versus-leukemia effect (GVL) to eradicate residual tumor cells by immunologic mechanisms. However, graft-versus-host disease (GVHD) remains the major toxicity of allo-HSCT. Alloreactive donor T cells are important effector cells in the development of GVHD, and proinflammatory cytokines enhance the generation of donor antihost cytotoxic function. Myeloid differentiation factor (MyD88) is a cytoplasmic adaptor molecule essential for integrating and transducing the signals generated by the Toll-like receptor (TLR) family. TLR engagement on professional antigen-presenting cells induces their maturation, resulting in optimal T-cell activation. However, recent advances indicate that the adjuvant effects of certain TLR agonists may also be attributed to the activation of TLRs and MyD88 directly in T cells. Both CD4 and CD8 T cells express functional TLRs. It remains to be defined whether direct TLR signaling on donor T cells is critical for GVHD or GVL activity. We used C57BL/6 (H-2b) → B6D2F1 (H-2b/d) experimental allo-HSCT model, which differs at major and minor histocompatibility loci, to address the role of donor T cell MyD88 signaling on GVHD and GVL. Lethally irradiated recipient mice were transplanted TCD-BM (5 × 106) together with either wild-type (WT) or MyD88 knock out (KO) mice spleen T cells (1 × 106) on day 0 and then host-type P815 mastocytoma or L1210 leukemia (H-2d) cells were injected either intravenously (3 × 103) or subcutaneously (1 × 106) on day 1 to generate a GVHD/GVL model. First of all, clinical GVHD scores were comparable between recipients of WT T cells and MyD88 KO T cells. At 70 days post-allo-HSCT, 50 % of allogeneic recipients of WT T cells died due to severe GVHD, but necropsy showed no evidence of tumor. In contrast, 83.5% of those of MyD88 KO T cells died with gross evidence of tumors (P<.05). Moreover, subcutaneous tumors in the allogeneic recipients receiving MyD88 KO T cells exhibited markedly increased growth in vivo compared to those receiving WT T cells (tumor volume on day 41, 15205.6 vs. 373.9 mm3, P<.01). GVHD mortality is critically dependent on donor CD4 T cells in this donor/recipient strain combination (B6 → B6D2F1) and CD8 T cells that mediate cytotoxicity are more potent effectors of GVL. The percentages of donor T cells to undergo proliferation or apoptosis in response to alloantigens in vivo between the two T cell types was examined; apoptosis of CD8 T cells in recipients of MyD88 KO T cells was significantly enhanced compared to those of WT T cell recipients (P<.01) whereas apoptosis of CD4 T cells was comparable between two groups. Resultingly, the percentages of CD8 T cells in recipients of MyD88 KO T cells were significantly lower (P<.01). We next examined the effects of MyD88 signaling in donor T cells on cytolytic activity to host antigens. Splenocytes harvested from WT mice showed stronger cytolytic activity against P815 targets compared to those from MyD88 KO mice (P<.01). After allogeneic mixed leukocyte reaction, responder T cells from MyD88 KO mice showed markedly reduced IFN-γ, MCP-1 and IL-17A production with a significant augmentation in IL-10 secretion. We further evaluated the effect of T-cell MyD88 deficiency on GVL mediated by the intensity of total body irradiation (TBI) conditioning (1300 vs. 900 cGy, Exp Hematol 2011; 39: 1018–29). Enhanced GVL in the allogeneic recipients receiving 1300 cGy TBI was not shown in the recipients of MyD88 KO T cells. In summary, these results highlight a critical role for MyD88 signaling in T-cell activation and cytotoxicity, offering the opportunity for improving GVL activity by targeting TLR-MyD88 signaling within donor T cells. Furthermore, these data demonstrated that MyD88 deficiency in T cells can impair cytolytic function or subsequent GVL activity of CD8 T cells without significant change in the severity of CD4-dependent GVHD. This difference is attributed to the fact that MyD88 deficiency in T cells causes an enhanced apoptosis of donor CD8 T cells but not donor CD4 T cells in vivo after HSCT. Disclosures: No relevant conflicts of interest to declare.

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