Faculty Opinions recommendation of CXCR5(+) follicular cytotoxic T cells control viral infection in B cell follicles.

Abstract In patients with B-cell chronic lymphocytic leukemia (B-CLL), the absolute number of T cells is increased. Although it has been suggested that these T cells might be tumor specific, concrete evidence for this hypothesis is lacking. We performed a detailed immunophenotypic analysis of the T-cell compartment in the peripheral blood of 28 patients with B-CLL (Rai 0, n = 12; Rai I-II, n = 10; Rai III-IV, n = 6) and 12 healthy age-matched controls and measured the ability of these patients to mount specific immune responses. In all Rai stages a significant increase in the absolute numbers of CD3+ cells was observed. Whereas the number of CD4+ cells was not different from controls, patients with B-CLL showed significantly increased relative and absolute numbers of CD8+ cells, which exhibited a CD45RA+CD27- cytotoxic phenotype. Analysis of specific immune responses with tetrameric cytomegalovirus (CMV)–peptide complexes showed that patients with B-CLL had significantly increased numbers of tetramer-binding CMV-specific CD8+ T cells. The rise in the total number of CD8+ cytotoxic T cells was evident only in CMV-seropositive B-CLL patients. Thus, our data suggest that in patients with B-CLL the composition of T cells is shifted toward a CD8+ cytotoxic cell type in an effort to control infections with persistent viruses such as CMV. Moreover, they offer an explanation for the high incidence of CMV reactivation in CLL patients treated with T cell–depleting agents, such as the monoclonal antibody (mAb) alemtuzumab (Campath; α-CD52 mAb). Furthermore, because in CMV-seronegative patients no increase in cytotoxic CD8+ T cells is found, our studies do not support the hypothesis that tumor-specific T cells account for T-cell expansion in B-CLL.

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Redirection of CMV Specific CTL towards B-CLL Via CD20 Targeted HLA/CMV Complexes.

Blood ◽

10.1182/blood.v106.11.449.449 ◽

2005 ◽

Vol 106 (11) ◽

pp. 449-449 ◽

Cited By ~ 3

Author(s):

Rogier Mous ◽

Philip Savage Savage ◽

Ester BM Remmerswaal ◽

Rene A.W. van Lier ◽

Eric Eldering ◽

...

Keyword(s):

T Cells ◽

B Cell ◽

Immunological Synapse ◽

Ex Vivo ◽

Cytotoxic T Cells ◽

Interferon Γ ◽

Lymphocytic Leukemia ◽

Viral Immunity ◽

Single Chain ◽

Effector Cells

Abstract Because B cell chronic lymphocytic leukemia (B-CLL) can not be cured with current therapies, but in general has a slow progression and rather long median survival, it is considered an attractive candidate for active T cell mediated immunotherapy. However B-CLL cells have poor antigen presenting capacity because they express low levels of co-stimulatory molecules. Moreover, most immunotherapeutic strategies require knowledge of the eliciting tumor antigen and/or ex vivo manipulation of patient cells. To circumvent these drawbacks we aim to redirect existing viral immunity towards B-CLL. Previously, we have shown that in patients with B-CLL considerably expanded numbers of cytomegalovirus (CMV)-specific CD45RA+CD27 CD8+ cytotoxic T cells are present (W. Mackus et al. Blood2003; 102:1057). These cells are potent cytotoxic effector cells when directed against B-CLL cells loaded with CMV peptide (A.Kater et al. Br.J. Haematol.2004; 126:512). In the current study, we apply a novel bridging reagent to redirect CMV-specific CTL to specifically target B-CLL. The targeting complex is composed of a streptavidin fused anti-CD20 single chain variable fragment (scFv) in combination with biotinylated MHC class I molecules containing CMV pp65 peptide (HLA/CMV). We demonstrate that this complex is stable on the cell surface for ≥24 hours, and that B-CLL cells coated with this CD20-HLA/CMV complex can be lysed by autologous CMV-specific CD8+ CTL with similar efficiency as B-CLL cells directly loaded with CMV-peptide. Killing occurs at scFv CD20 concentrations of ≥100 ng ml−1 and HLA/CMV concentrations of ≥20 ng ml−1. Lysis of CD20-HLA/CMV complex coated CLL cells could not be blocked by anti-LFA1 antibodies, in contrast to B-CLL cells directly loaded with CMV-peptide, indicating a different immunological synapse. HLA-A2 positive B-CLL cells coated with HLA-B7 /CMV complexes were only lysed by HLA-B7 positive CMV-specific CTL, whereas HLA-A2/CMV complex targeted HLA-A2 positive B-CLL cells were unaffected by HLA-B7 positive CMV specific CTL, proving HLA restriction of the killing.. Furthermore, CD20-HLA/CMV complex coated B-CLL cells induce both proliferation and cytokine production (interferon γ, tumor necrosis factor α, and macrophage inflammatory protein-1 β) in CMV-specific CD8+ T cells. Thus, CD20-HLA/CMV complexes elicit both immune activation and direct cytotoxicity towards B-CLL cells. The findings of our study constitute a necessary step towards possible application of CD20-HLA/CMV complexes for immunotherapy of B cell malignancies. It is obvious that this recently recognized capacity to redirect existing antiviral immunity towards tumor cells has a utility in cancer immunotherapy far beyond CMV and B-CLL.

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Protection against immunopathological consequences of a viral infection by activated but not resting cytotoxic T cells: T cell memory without "memory T cells"?

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.94.2.640 ◽

1997 ◽

Vol 94 (2) ◽

pp. 640-645 ◽

Cited By ~ 95

Author(s):

M. F. Bachmann ◽

T. M. Kundig ◽

H. Hengartner ◽

R. M. Zinkernagel

Keyword(s):

T Cells ◽

T Cell ◽

Viral Infection ◽

Memory T Cells ◽

Cytotoxic T Cells ◽

T Cell Memory ◽

Cell Memory

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Engineered FVIII-expressing cytotoxic T cells target and kill FVIII-specific B cells in vitro and in vivo

Blood Advances ◽

10.1182/bloodadvances.2018018556 ◽

2018 ◽

Vol 2 (18) ◽

pp. 2332-2340 ◽

Cited By ~ 17

Author(s):

Kalpana Parvathaneni ◽

David W. Scott

Keyword(s):

T Cells ◽

B Cells ◽

B Cell ◽

Cd8 T Cells ◽

Hemophilia A ◽

Cytotoxic T Cells ◽

Cell Antibody ◽

Engineered T Cells

Abstract Hemophilia A is an X-linked bleeding disorder caused by mutations in the factor VIII (FVIII) gene (F8). Treatment with recombinant or plasma-derived FVIII replacement therapy is standard therapy. A major problem in treating hemophilia A patients with therapeutic FVIII is that 20% to 30% of these patients produce neutralizing anti-FVIII antibodies (inhibitors) because they are not immunologically tolerant to this human protein. Hence, there is a need to establish tolerogenic protocols to FVIII epitopes. To specifically target FVIII-specific B cells, we engineered immunodominant FVIII domains (A2 and C2) as a chimeric antigen receptor expressed by both human and murine cytotoxic T cells. This FVIII domain engineered B-cell antibody receptor (BAR) that expresses T cells was capable of killing FVIII-reactive B-cell hybridomas in vitro and in vivo. Moreover, FVIII BAR CD8 T cells blocked the development of specific antibody from unimmunized spleen cells stimulated polyclonally with lipopolysaccharide in vitro. In addition, adoptive transfer of FVIII A2- and C2-BAR CD8 T cells significantly reduced the anti-FVIII antibody formation in hemophilic mice. These data suggest that BAR-engineered T cells are a promising approach for future prophylactic treatment for patients with severe hemophilia A who are at high risk of developing inhibitors.

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Viral induction and targeted inhibition of galectin-1 in EBV+ posttransplant lymphoproliferative disorders

Blood ◽

10.1182/blood-2010-11-320481 ◽

2011 ◽

Vol 117 (16) ◽

pp. 4315-4322 ◽

Cited By ~ 54

Author(s):

Jing Ouyang ◽

Przemyslaw Juszczynski ◽

Scott J. Rodig ◽

Michael R. Green ◽

Evan O'Donnell ◽

...

Keyword(s):

T Cells ◽

B Cell ◽

Cytotoxic T Cells ◽

Treatment Strategies ◽

Lymphoproliferative Disorders ◽

Luciferase Expression ◽

Carbohydrate Binding ◽

Solid Organ ◽

Hematopoietic Stem ◽

Posttransplant Lymphoproliferative Disorders

Abstract Posttransplant lymphoproliferative disorders (PTLDs) are potentially fatal, EBV-driven B-cell malignancies that develop in immunocompromised solid organ or hematopoietic stem cell recipients. In PTLD, the expression of EBV proteins, including latent membrane protein 1 (LMP1) and LMP2A, viral immune evasion strategies, and impaired host immune surveillance foster the proliferation of EBV-transformed B cells. Current PTLD treatment strategies include reduction of immunosuppression, which increases the risk of graft rejection, anti-CD20 treatment, combination chemotherapy, and administration of EBV-specific cytotoxic T cells. In the present study, we report that EBV-transformed lymphoblastoid B-cell lines (LCLs) and primary PTLDs overexpress galectin-1 (Gal1), a carbohydrate-binding lectin that induces tolerogenic dendritic cells and triggers the selective apoptosis of CD4+ Th1 and Th17 cells and cytotoxic T cells. In transcriptional reporter assays, LMP2A and LMP1 each increased Gal1-driven luciferase expression, and the combination of LMP2A and LMP1 was additive. In addition, small interfering RNA (siRNA)–mediated depletion of LMP2A decreased Gal1 protein abundance in EBV-transformed LCLs. Gal1 expression in LCLs was dependent on both activating protein 1 (AP-1) and PI3K. A newly developed neutralizing Gal1 mAb selectively inhibited Gal1-mediated apoptosis of EBV-specific CD8+ T cells. Given the tolerogenic and immunosuppressive function of Gal1, antibody-mediated Gal1 neutralization may represent a novel immunotherapeutic strategy for PTLD and other Gal1-expressing tumors.

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