Browsing by Author "Yigit, Burcu"

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    The Checkpoint Regulator SLAMF3 Preferentially Prevents Expansion of Auto-Reactive B Cells Generated by Graft-vs.-Host Disease
    (Frontiers, 2019-04-17) Wang, Ninghai; Yigit, Burcu; van der Poel, Cees E.; Cuenca, Marta; Carroll, Michael C.; Herzog, Roland W.; Engel, Pablo; Terhorst, Cox; Pediatrics, School of Medicine
    Absence of the mouse cell surface receptor SLAMF3 in SLAMF3-/- mice suggested that this receptor negatively regulates B cell homeostasis by modulating activation thresholds of B cell subsets. Here, we examine whether anti-SLAMF3 affects both B and T cell subsets during immune responses to haptenated ovalbumin [NP-OVA] and in the setting of chronic graft vs. host disease (cGVHD) induced by transferring B6.C-H2 bm12/KhEg (bm12) CD4+ T cells into B6 WT mice. We find that administering αSLAMF3 to NP-OVA immunized B6 mice primarily impairs antibody responses and Germinal center B cell [GC B] numbers, whilst CXCR5+, PD-1+, and ICOS+ T follicular helper (TFH) cells are not significantly affected. By contrast, administering αSLAMF3 markedly enhanced autoantibody production upon induction of cGVHD by the transfer of bm12 CD4+ T cells into B6 recipients. Surprisingly, αSLAMF3 accelerated both the differentiation of GC B and donor-derived TFH cells initiated by cGVHD. The latter appeared to be induced by decreased numbers of donor-derived Treg and T follicular regulatory (TFR) cells. Collectively, these data show that control of anti-SLAMF3-induced signaling is requisite to prevent autoantibody responses during cGVHD, but reduces responses to foreign antigens.
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    SLAMF6 as a Regulator of Exhausted CD8+ T Cells in Cancer
    (AACR, 2019-09) Yigit, Burcu; Wang, Ninghai; ten Hacken, Elisa; Chen, Shih-Shih; Bhan, Atul K.; Suarez Fueyo, Abel; Katsuyama, Eri; Tsokos, George C.; Chiorazzi, Nicholas; Wu, Catherine J.; Burger, Jan A.; Herzog, Roland W.; Engel, Pablo; Terhorst, Cox; Pediatrics, School of Medicine
    The tumor microenvironment in leukemia and solid tumors induces a shift of activated CD8+ cytotoxic T cells to an exhausted state, characterized by loss of proliferative capacity and impaired immunologic synapse formation. Efficient strategies and targets need to be identified to overcome T-cell exhaustion and further improve overall responses in the clinic. Here, we took advantage of the Eμ-TCL1 chronic lymphocytic leukemia (CLL) and B16 melanoma mouse models to assess the role of the homophilic cell-surface receptor SLAMF6 as an immune-checkpoint regulator. The transfer of SLAMF6+ Eμ-TCL1 cells into SLAMF6−/− recipients, in contrast to wild-type (WT) recipients, significantly induced expansion of a PD-1+ subpopulation among CD3+CD44+CD8+ T cells, which had impaired cytotoxic functions. Conversely, administering anti-SLAMF6 significantly reduced the leukemic burden in Eμ-TCL1 recipient WT mice concomitantly with a loss of PD-1+CD3+CD44+CD8+ T cells with significantly increased effector functions. Anti-SLAMF6 significantly reduced leukemic burden in the peritoneal cavity, a niche where antibody-dependent cellular cytotoxicity (ADCC) is impaired, possibly through activation of CD8+ T cells. Targeting of SLAMF6 affected tumor growth not only in B cell–related leukemia and lymphomas but also in nonhematopoietic tumors such as B16 melanoma, where SLAMF6 is not expressed. In vitro exhausted CD8+ T cells showed increased degranulation when anti-human SLAMF6 was added in culture. Taken together, anti-SLAMF6 both effectively corrected CD8+ T-cell dysfunction and had a direct effect on tumor progression. The outcomes of our studies suggest that targeting SLAMF6 is a potential therapeutic strategy.
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    SLAMF6 in health and disease: Implications for therapeutic targeting
    (Elsevier, 2018) Yigit, Burcu; Wang, Ninghai; Herzog, Roland W.; Terhorst, Cox; Pediatrics, School of Medicine