scholarly journals MyD88 Costimulation in Donor CD8+ T Cells Enhances the Graft-versus-Tumor Effect in Murine Hematopoietic Cell Transplantation

2021 ◽  
pp. ji2000479
Author(s):  
Nicholas G. Ciavattone ◽  
Long Wu ◽  
Rachel O’Neill ◽  
Jingxin Qiu ◽  
Eduardo Davila ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Transplantation ◽  
Cd8 T Cells ◽  
Hematopoietic Cell Transplantation ◽  
Hematopoietic Cell ◽  
Graft Versus Tumor Effect

Characterization of NK1.1+ CD8 T Cells in Allogeneic Hematopoietic Cell Transplantation Recipients

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4616-4616
Author(s):  
Yi Wang ◽  
Hui Wang ◽  
Shumei Wang ◽  
Megan Sykes ◽  
Yong-Guang Yang
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Cell Transplantation ◽  
Cd8 T Cells ◽  
Hematopoietic Cell Transplantation ◽  
Flow Cytometric Analysis ◽  
Nkt Cells ◽  
Hematopoietic Cell ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
Memory Phenotype

Abstract NKT cells from naïve mice are mainly CD4+ or CD4−CD8−. However, it has been reported that CD8+ NKT cells can be expanded in vitro from splenocytes, bone marrow cells and thymocytes of C57BL/6 (B6) mice by stimulation with anti-CD3 mAb and cytokines, and that the expanded CD8+ NKT cells mediate strong graft-vs.-leukemic (GVL) effects without severe GVHD after adoptive transfer into allogeneic mice. We now describe the presence of CD8+NK1.1+ cells in recipient livers (approximately 2–6%), but not in other tissues (spleen, lung, bone marrow, thymus and PBMC), in various allogeneic hematopoietic cell transplantation (allo-HCT) models. The generation of CD8+NK1.1+ cells is likely a consequence of alloresponses, as these cells were not detected in the liver of syngeneic HCT controls. Flow cytometric analysis confirmed that these cells are CD1d-independent, TCRαβ+ T cells with a memory phenotype (CD44+ and CD62L−), and do not express CD49b, Ly-49C/I, Ly-49G2, or Ly-49D. In a sublethally (6 Gy)-irradiated B6-to-B6D2F1 allo-HCT model, NK1.1+ CD8 T cells became detectable by week 2, increased in number until approximately week 8, and gradually declined thereafter but were still detectable in the liver at day 100 after allo-HCT. By using CD45.1 and CD45.2 congeneic donors, we determined that the majority of NK1.1+ CD8 T cells were derived from the donor splenocytes. Furthermore, depletion of CD8+, but not NK1.1+, cells from the donor splenocytes prior to transplantation prevented the generation of NK1.1+ CD8 T cells, indicating that these cells were derived from donor NK1.1−CD8+ splenic T cells. Our data demonstrate that donor CD8 T cells can acquire NK1.1 expression upon activation in allo-HCT recipients, and that these NK1.1+ CD8 T cells maintain a memory phenotype and persist in the recipients with preferential accumulation in the liver. Studies are currently in progress to determine the role of activated donor NK1.1+ CD8 T cells in GVHD and GVL effects.

Evidence for Involvement of Clonally Expanded CD8+ T Cells in Anti-Cancer Immune Responses in CLL Patients Following Nonmyeloablative Conditioning and Hematopoietic Cell Transplantation (HCT).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1260-1260
Author(s):  
Tania Kollgaard ◽  
Soren L. Petersen ◽  
Sine Reker Hadrup ◽  
Tania N. Masmas ◽  
Tina Seremet ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Transplantation ◽  
Cd8 T Cells ◽  
Hematopoietic Cell Transplantation ◽  
Hematopoietic Cells ◽  
Cd8 T Cell ◽  
Hematopoietic Cell ◽  
Cell Surface Expression ◽  
High Morbidity

Abstract Allogeneic hematopoietic cell transplantation (HCT) has a well-documented ability to cure a number of malignant hematological diseases. The curative principle in allogeneic HCT is the Graft-versus-Leukemia (GVL) effect and nonmyeloablative (NMA) conditioning HCT relies exclusively on this anti-tumor effect to eliminate tumor cells. Donor T-cells are documented to be responsible for the GVL effect, however, often they also cause Graft-versus-Host disease (GVHD) which is associated with high morbidity and mortality. Characterization of cells and molecules involved in both GVL and GVHD would potentially set the stage for separation of GVL and GVHD in order to augment GVL in the absence of GVHD. In the present study, we analyzed the clonotype composition of CD8+ T cells following NMA conditioning and HCT, in two patients with chronic lymphocytic leukemia (CLL). T-cell receptor (TCR) clonotype mapping (RT-PCR combined with denaturing gradient gel electrophoresis (DGGE)) was used to identify clonally expanded CD8+ T cells in blood samples. This method provides a “molecular fingerprint” of each unique T cell based on junctional diversity of the TCR CDR3 region and, thus, offers the means to track T-cell clonotypes in time and space. Longitudinal comparative analyses showed that CD8+ T-cell clonality was highly dynamic during early phases after transplantation with various clonotypes emerging and disappearing. However, clonal diversity decreased after 4–5 months and stable CD8+ T-cell clonotypes appeared and persisted throughout the analyzed period (up to two years). One patient received donor lymphocyte infusion (DLI) due to disease progression and this was shown to lead to establishment of recurrent (detected prior to DLI) CD8+ T-cell clonotypes as well as new CD8+ T-cell clonotypes. The appearance of these cells correlated with disease remission strongly suggesting their engagement in anti-CLL reactivity. To examine the functional capacities of clonally expanded T cells after HCT, recipient CD8+ T cells were stimulated ex vivo with pre-transplant patient CLL cells and/or normal hematopoietic cells and the T-cell surface expression of CD107a (marker for cytotoxicity) was detected by FACS. Clonotype mapping analyses of FACS sorted CD107a positive CD8+ T cells after stimulation with CLL cells demonstrated that such cytotoxic CD8+ T cells were present as stable clonally expanded T cells in vivo strongly implying their involvement in an ongoing anti-CLL-response. Furthermore, co-culture with normal hematopoietic cells resulted in a unique CD107a positive expanded T-cell clonotype. Our results strongly suggest that clonally expanded CD8+ T cells are involved in an ongoing tumor response and support data which demonstrate that GVL and GVHD are the result of distinct responses.

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