Clonal expansion of CD8+ T cells reflects graft-versus-leukemia activity and precedes durable remission following DLI

Donor lymphocyte infusion (DLI) is a standard of care for relapse of AML after allogeneic hematopoietic stem cell transplantation (aHSCT). Currently it is poorly understood how and when CD8+ αβ T cells exert graft-versus-leukemia (GvL) activity after DLI. Also, there is no reliable biomarker to monitor GvL activity of the infused CD8+ T cells. Therefore, we analyzed the dynamics of CD8+ αβ T cell clones in DLI-patients. In this prospective clinical study of 29 patients, we performed deep T cell receptor β (TRB) sequencing of sorted CD8+ αβ T cells to track patients' repertoire changes in response to DLI. Upon first occurrence of GvL, longitudinal analyses revealed a preferential expansion of distinct CD8+ TRB clones (n=14). This did not occur in samples of patients without signs of GvL (n=11). Importantly, early repertoire changes 15 days after DLI predicted durable remission for the 36 months study follow-up. Furthermore, absence of clonal outgrowth of the CD8+ TRB repertoire after DLI was an early biomarker that predicted relapse at a median time of 11.2 months ahead of actual diagnosis. Additionally, unbiased sample analysis regardless of the clinical outcome revealed that patients with decreasing CD8+ TRB diversity at day 15 after DLI (n=13) had a lower relapse incidence (P=0.0040) compared to patients without clonal expansion (n=6). In conclusion, CD8+ TRB analysis may provide a reliable tool for predicting the efficacy of DLI and holds the potential to identify patients at risk for progression and relapse after DLI.

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Cytomegalovirus-Specific CD8+ T-Cells With Different T-Cell Receptor Affinities Segregate T-Cell Phenotypes and Correlate With Chronic Graft-Versus-Host Disease in Patients Post-Hematopoietic Stem Cell Transplantation

Frontiers in Immunology ◽

10.3389/fimmu.2018.00760 ◽

2018 ◽

Vol 9 ◽

Cited By ~ 4

Author(s):

Thomas Poiret ◽

Rebecca Axelsson-Robertson ◽

Mats Remberger ◽

Xiao-Hua Luo ◽

Martin Rao ◽

...

Keyword(s):

T Cells ◽

Stem Cell ◽

T Cell ◽

T Cell Receptor ◽

Cd8 T Cells ◽

Cell Receptor ◽

Hematopoietic Stem ◽

Graft Versus Host ◽

T Cell Phenotypes ◽

Cell Phenotypes

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Frequent occurrence ofin vivo clonal expansion of CD4− CD8− T cells bearing T cell receptor αβ chains in adult humans

European Journal of Immunology ◽

10.1002/eji.1830231102 ◽

1993 ◽

Vol 23 (11) ◽

pp. 2735-2739 ◽

Cited By ~ 6

Author(s):

Yoichiro Kusunoki ◽

Yuko Hirai ◽

Tomonori Hayashi ◽

Seishi Kyoizumi ◽

Keiko Takahashi ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Receptor ◽

Cd8 T Cells ◽

Clonal Expansion ◽

Cell Receptor ◽

Frequent Occurrence ◽

Adult Humans

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Blockade of osteopontin reduces alloreactive CD8+ T cell–mediated graft-versus-host disease

Blood ◽

10.1182/blood-2010-04-281659 ◽

2011 ◽

Vol 117 (5) ◽

pp. 1723-1733 ◽

Cited By ~ 21

Author(s):

Fang Zhao ◽

Yi Zhang ◽

Hao Wang ◽

Min Jin ◽

Shan He ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Graft Versus Host Disease ◽

Cd8 T Cells ◽

Cd8 T Cell ◽

Cell Receptor ◽

Hematopoietic Stem ◽

Host Disease ◽

Graft Versus Host ◽

Donor T Cells

Abstract Graft-versus-host disease (GVHD), a life-threatening complication after allogeneic hematopoietic stem cell transplantation, is caused by alloreactive donor T cells that trigger host tissue damage. The inflammatory environment inside recipients is critical for GVHD pathogenesis, but the underpinning mechanisms remain elusive. Using mouse model of human GVHD, we demonstrate osteopontin (OPN), a potent proinflammatory cytokine, plays an important role in regulating activation, migration, and survival of alloreactive T cells during GVHD. OPN was significantly elevated after irradiation and persisted throughout the course of GVHD. Blockade of OPN attenuated GVHD with reduced accumulation of donor T cells in recipient organs. Amelioration was the result of migration and survival suppression caused by anti-OPN treatment on donor-derived T cells for 2 reasons. First, OPN promoted the migration and infiltration of naive and alloreactive CD8+ T cells into host organs. Second, it also facilitated activation and viability of donor-derived CD8+ T cells via synergizing with T-cell receptor/CD3 signaling. Finally, anti-OPN treatment retained graft-versus-leukemia effect of alloreactive CD8+ T cells. This study demonstrates, to our knowledge for the first time, the critical effect of OPN in the initiation and persistence of CD8+ T cell-mediated GVHD and validates OPN as a potential target in GVHD prevention.

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PD-L1 blockade effectively restores strong graft-versus-leukemia effects without graft-versus-host disease after delayed adoptive transfer of T-cell receptor gene-engineered allogeneic CD8+ T cells

Blood ◽

10.1182/blood-2010-04-283119 ◽

2011 ◽

Vol 117 (3) ◽

pp. 1030-1041 ◽

Cited By ~ 54

Author(s):

Wolfgang Koestner ◽

Martin Hapke ◽

Jessica Herbst ◽

Christoph Klein ◽

Karl Welte ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Receptor ◽

Graft Versus Host Disease ◽

Cd8 T Cells ◽

Adoptive Transfer ◽

Cell Receptor ◽

Graft Versus Host ◽

Graft Versus Leukemia

Abstract Adoptive transfer (AT) of T cells forced to express tumor-reactive T-cell receptor (TCR) genes is an attractive strategy to direct autologous T-cell immunity against tumor-associated antigens. However, clinical effectiveness has been hampered by limited in vivo persistence. We investigated whether the use of major histocompatibility complex–mismatched T cells would prolong the in vivo persistence of tumor-reactive TCR gene expressing T cells by continuous antigen-driven proliferation via the endogenous potentially alloreactive receptor. Donor-derived CD8+ T cells engineered to express a TCR against a leukemia-associated antigen mediated strong graft-versus-leukemia (GVL) effects with reduced graft-versus-host disease (GVHD) severity when given early after transplantation. AT later after transplantation resulted in a complete loss of GVL. Loss of function was associated with reduced expansion of TCR-transduced T cells as assessed by CDR3 spectratyping analysis and PD-1 up-regulation on T cells in leukemia-bearing recipients. PD-L1 blockade in allogeneic transplant recipients largely restored the GVL efficacy without triggering GVHD, whereas no significant antileukemia effects of PD-L1 blockade were observed in syngeneic controls. These data suggest a clinical approach in which the AT of gene-modified allogeneic T cells early after transplantation can provide a potent GVL effect without GVHD, whereas later AT is effective only with concurrent PD-L1 blockade.

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Replacement therapy with plasma-derived factor VIII concentrates induces skew in T-cell receptor usage and clonal expansion of CD8+ T-cell in HIV-seronegative hemophilia patients

Thrombosis and Haemostasis ◽

10.1160/th02-12-0302 ◽

2003 ◽

Vol 90 (08) ◽

pp. 279-292 ◽

Cited By ~ 9

Author(s):

Takaji Matsutani ◽

Yoshihiko Sakurai ◽

Takeshi Yoshioka ◽

Yuji Tsuruta ◽

Ryuji Suzuki ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Factor Viii ◽

Replacement Therapy ◽

T Cell Receptor ◽

Cd8 T Cells ◽

Clonal Expansion ◽

Cell Receptor ◽

T Cell Clonality ◽

Cell Clonality

SummaryReplacement therapy with factor VIII (FVIII) products causes immune abnormalities in human immunodeficiency virus (HIV)-seronegative hemophilia patients. However, the question remains why an absolute increase in the number of CD8+ T-cells and diminished proliferation responses of lymphocytes to antigen stimulation in vitro occurs in HIV-seronegative hemophilia patients.To examine whether the FVIII products induce skewing of T-cell receptor (TCR) repertoires, TCR variable region α-chain and β–chain repertoires were analyzed for peripheral blood mononuclear cells (PBMCs) from 15 hemophilia patients treated with heated and/or non-heated plasma-derived FVIII concentrates and 10 age-matched healthy adults. Also, T-cell clonality was compared between these groups using complementarity-determining region 3 (CDR3) size spectratyping. The skewing of TCR repertoires was significantly greater for hemophilia patients than healthy controls. The extent of T-cell clonality was greater for hemophilia patients than the controls, indicating that clonal T-cells frequently expanded in hemophilia patients. The skew in TCR usage and clonal expansion were primarily observed in patients treated with non-heated plasma-derived products.The spectratyping and sequencing of CDR3 regions revealed that the clonal expansion of T-cells was observed for CD8+ T-cells, but not CD4+ T-cells.These results suggest that extensive expansion of CD8+ T-cells is induced by some viruses other than HIV present in FVIII preparations, and the resulting accumulation of CD8+ T-cells is responsible for changes in peripheral T-cell population in HIV-seronegative hemophilia patients.

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