Nelly Malenkovich
Harvard University
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Publication
Featured researches published by Nelly Malenkovich.
Nature Immunology | 2001
Yvette Latchman; Clive Wood; Tatyana Chernova; Divya Chaudhary; Madhuri Borde; Irene Chernova; Yoshiko Iwai; Andrew J. Long; Julia Brown; Raquel Nunes; Edward A. Greenfield; Karen Bourque; Vassiliki A. Boussiotis; Laura Carter; Beatriz M. Carreno; Nelly Malenkovich; Hiroyuki Nishimura; Taku Okazaki; Tasuku Honjo; Arlene H. Sharpe; Gordon J. Freeman
Programmed death 1 (PD-1)–deficient mice develop a variety of autoimmune-like diseases, which suggests that this immunoinhibitory receptor plays an important role in tolerance. We identify here PD-1 ligand 2 (PD-L2) as a second ligand for PD-1 and compare the function and expression of PD-L1 and PD-L2. Engagement of PD-1 by PD-L2 dramatically inhibits T cell receptor (TCR)-mediated proliferation and cytokine production by CD4+ T cells. At low antigen concentrations, PD-L2–PD-1 interactions inhibit strong B7-CD28 signals. In contrast, at high antigen concentrations, PD-L2–PD-1 interactions reduce cytokine production but do not inhibit T cell proliferation. PD-L–PD-1 interactions lead to cell cycle arrest in G0/G1 but do not increase cell death. In addition, ligation of PD-1 + TCR leads to rapid phosphorylation of SHP-2, as compared to TCR ligation alone. PD-L expression was up-regulated on antigen-presenting cells by interferon γ treatment and was also present on some normal tissues and tumor cell lines. Taken together, these studies show overlapping functions of PD-L1 and PD-L2 and indicate a key role for the PD-L–PD-1 pathway in regulating T cell responses.
Nature | 2001
Alexander J. McAdam; Rebecca J. Greenwald; Michele A. Levin; Tatyana Chernova; Nelly Malenkovich; Vincent Ling; Gordon J. Freeman; Arlene H. Sharpe
The inducible co-stimulatory molecule (ICOS) is a CD28 homologue implicated in regulating T-cell differentiation. Because co-stimulatory signals are critical for regulating T-cell activation, an understanding of co-stimulatory signals may enable the design of rational therapies for immune-mediated diseases. According to the two-signal model for T-cell activation, T cells require an antigen-specific signal and a second, co-stimulatory, signal for optimal T-cell activation. The co-stimulatory signal promotes T-cell proliferation, lymphokine secretion and effector function. The B7–CD28 pathway provides essential signals for T-cell activation, but does not account for all co-stimulation. We have generated mice lacking ICOS (ICOS-/- ) to determine the essential functions of ICOS. Here we report that ICOS-/- mice exhibit profound deficits in immunoglobulin isotype class switching, accompanied by impaired germinal centre formation. Class switching was restored in ICOS-/- mice by CD40 stimulation, showing that ICOS promotes T-cell/B-cell collaboration through the CD40/CD40L pathway.
Journal of Immunology | 2000
Alexander J. McAdam; Tammy T. Chang; Anna E. Lumelsky; Edward A. Greenfield; Vassiliki A. Boussiotis; Jonathan S. Duke-Cohan; Tatyana Chernova; Nelly Malenkovich; Claudia Jabs; Vijay K. Kuchroo; Vincent Ling; Mary Collins; Arlene H. Sharpe; Gordon J. Freeman
The inducible costimulatory (ICOS) molecule is expressed by activated T cells and has homology to CD28 and CD152. ICOS binds B7h, a molecule expressed by APC with homology to CD80 and CD86. To investigate regulation of ICOS expression and its role in Th responses we developed anti-mouse ICOS mAbs and ICOS-Ig fusion protein. Little ICOS is expressed by freshly isolated mouse T cells, but ICOS is rapidly up-regulated on most CD4+ and CD8+ T cells following stimulation of the TCR. Strikingly, ICOS up-regulation is significantly reduced in the absence of CD80 and CD86 and can be restored by CD28 stimulation, suggesting that CD28-CD80/CD86 interactions may optimize ICOS expression. Interestingly, TCR-transgenic T cells differentiated into Th2 expressed significantly more ICOS than cells differentiated into Th1. We used two methods to investigate the role of ICOS in activation of CD4+ T cells. First, CD4+ cells were stimulated with beads coated with anti-CD3 and either B7h-Ig fusion protein or control Ig fusion protein. ICOS stimulation enhanced proliferation of CD4+ cells and production of IFN-γ, IL-4, and IL-10, but not IL-2. Second, TCR-transgenic CD4+ T cells were stimulated with peptide and APC in the presence of ICOS-Ig or control Ig. When the ICOS:B7h interaction was blocked by ICOS-Ig, CD4+ T cells produced more IFN-γ and less IL-4 and IL-10 than CD4+ cells differentiated with control Ig. These results demonstrate that ICOS stimulation is important in T cell activation and that ICOS may have a particularly important role in development of Th2 cells.
Journal of Experimental Medicine | 2000
Gordon J. Freeman; Andrew J. Long; Yoshiko Iwai; Karen Bourque; Tatyana Chernova; Hiroyuki Nishimura; Lori Fitz; Nelly Malenkovich; Taku Okazaki; Michael C. Byrne; Heidi F. Horton; Lynette A. Fouser; Laura Carter; Vincent Ling; Michael R Bowman; Beatriz M. Carreno; Mary Collins; Clive Wood; Tasuku Honjo
Archive | 2001
Gordon J. Freeman; Irene Chernova; Tatyana Chernova; Nelly Malenkovich; Clive Wood
Archive | 2000
Gordon J. Freeman; Vassiliki A. Boussiotis; Tatyana Chernova; Nelly Malenkovich
Archive | 2000
Gordon J. Freeman; Vassiliki A. Boussiotis; Tatyana Chernova; Nelly Malenkovich
Archive | 2006
Gordon J. Freeman; Vassiliki A. Boussiotis; Tatyana Chernova; Nelly Malenkovich
Archive | 2006
Gordon J. Freeman; Vassiliki A. Boussiotis; Tatyana Chernova; Nelly Malenkovich
Archive | 2007
Gordon J. Freeman; Irene Chernova; Tatyana Chernova; Nelly Malenkovich; Clive Wood