Karen Laky
National Institutes of Health
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Publication
Featured researches published by Karen Laky.
Journal of Immunology | 2010
Renee M. Laird; Karen Laky; Sandra M. Hayes
The Ag receptors on αβ and γδ T cells differ not only in the nature of the ligands that they recognize but also in their signaling potential. We hypothesized that the differences in αβ- and γδTCR signal transduction were due to differences in the intracellular signaling pathways coupled to these two TCRs. To investigate this, we used transcriptional profiling to identify genes encoding signaling molecules that are differentially expressed in mature αβ and γδ T cell populations. Unexpectedly, we found that B lymphoid kinase (Blk), a Src family kinase expressed primarily in B cells, is expressed in γδ T cells but not in αβ T cells. Analysis of Blk-deficient mice revealed that Blk is required for the development of IL-17–producing γδ T cells. Furthermore, Blk is expressed in lymphoid precursors and, in this capacity, plays a role in regulating thymus cellularity during ontogeny.
Current Opinion in Immunology | 2008
Karen Laky; B. J. Fowlkes
Because Notch often acts in concert with other signaling pathways, it is able to regulate a diverse set of biological processes in a cell-context dependent manner. In lymphocytes, Notch is essential for specifying the T cell fate and for promoting early stages of T cell differentiation. At later stages of development, Notch signaling is proposed to direct CD4 versus CD8 T lineage commitment. This hypothesis has been challenged by recent studies of conditional Presenilin-deficient mice showing that Notch promotes the selection and maturation of CD4 and CD8 T cells by potentiating TCR signal transduction in immature thymocytes. While similar conclusions have not been reported with conditional mutation of other downstream mediators of Notch activation, it appears that functional inhibition may not have been achieved at a comparable stage of development and/or analogous issues have not been addressed. The differences also question whether in thymocytes Notch signals only through the canonical pathway. Further study of conditional mutants, signaling intermediates, and transcriptional regulators are needed to elucidate how Notch facilitates TCR signaling in generating mature T cells.
Immunological Reviews | 2006
Karen Laky; Christine L. Fleischacker; B. J. Fowlkes
Summary: The generation of CD4 and CD8 αβ T‐cell lineages from CD4+CD8+ double‐positive (DP) thymocyte precursors is a complex process initiated by engagement of major histocompatibility complex (MHC) by T‐cell receptor (TCR) and coreceptor. Quantitative differences in TCR signaling induced by this interaction impose an instructional bias on CD4/CD8 lineage commitment that must be reinforced by MHC recognition and TCR signaling over subsequent selection steps in order for the thymocyte to progress and mature in the adopted lineage. Our studies show that the transmembrane receptor Notch plays a role in this process by modifying TCR signal transduction in DP thymocytes. In this review, we consider the functional relationship of TCR and Notch signaling pathways in the selection and specification of CD4 and CD8 T‐cell lineages.
International Immunology | 2009
Karen Laky; Willem Annaert; B. J. Fowlkes
Pharmacological inhibitors that block amyloid precursor protein (APP) cleavage and the formation of senile plaques are under development for the treatment of familial Alzheimers disease. Unfortunately, many inhibitors that block γ-secretase-mediated cleavage of APP also have immunosuppressive side effects. In addition to APP, numerous other proteins undergo γ-secretase-mediated cleavage. In order to develop safer inhibitors, it is necessary to determine which of the γ-secretase substrates contribute to the immunosuppressive effects. Because APP family members are widely expressed and are reported to influence calcium flux, transcription and apoptosis, they could be important for normal lymphocyte maturation. We find that APP and amyloid precursor-like protein 2 are expressed by stromal cells of thymus and lymph nodes, but not by lymphocytes. Although signals provided by thymic stromal cells are critical for normal T cell differentiation, lymphocyte development proceeds unperturbed in mice deficient for these APP family members.
Journal of Experimental Medicine | 2016
David G. Kugler; Francis A. Flomerfelt; Diego L. Costa; Karen Laky; Olena Kamenyeva; Ronald E. Gress; Stephan P. Rosshart; Barbara Rehermann; Jonathan D. Ashwell; Alan Sher; Dragana Jankovic
Kugler et al. show that systemic infection with Toxoplasma gondii triggers a long-term impairment in thymic function, which leads to an immunodeficient state reflected in decreased antimicrobial resistance.
Scientific Reports | 2018
Karen Laky; Philip Dugan; Pamela A. Frischmeyer-Guerrerio
Efficient hematopoietic reconstitution of wild type mice requires preconditioning. Established experimental protocols exist to transplant hematopoietic stem cells into lethally irradiated or chemically myeloablated adult mice or unirradiated immunodeficient mice. We sought to develop a protocol to reconstitute immuno-replete neonatal mice. We describe irradiation and injection procedures for two-day old mice that lead to efficient long-term reconstitution of primary and secondary lymphoid organs. We demonstrate that the frequencies of lymphoid and myeloid cells in primary and secondary lymphoid organs are indistinguishable from unirradiated uninjected sex- and age-matched control animals by 5 weeks post-reconstitution. Thus, this system will facilitate studies aimed at understanding the developmental and environmental mechanisms that contribute to conditions that have a window of susceptibility during the perinatal period.
Journal of Immunology | 2018
Kaveh Abdi; Karen Laky; Kartika Padhan; Constantinos Petrovas; Jeff Skinner; Juraj Kabat; David W. Dorward; Joseph A. Brzostowski; Eric O. Long; Giorgio Trinchieri; Rajat Varma
Early secretion of IL-12 by mouse dendritic cells (DCs) instructs T cells to make IFN-γ. However, only activated, but not naive T cells are able to license DCs for IL-12 production. We hypothesized that it might be due to different levels of CD40L expression on the surface of these cells, as CD40 signals are required for IL-12 production. Using quantitative cell-free systems incorporating CD40L in lipid bilayers combined with total internal reflection fluorescence microscopy and flow cytometry, we show that as low as ∼200 CD40L molecules/μm2 in combination with IL-4 is sufficient to induce IL-12 production by DCs. Remarkably, CD40L alone is adequate to induce IL-23 secretion by DCs. Thus, although activated T cells have somewhat higher levels of CD40L, it is the combination of CD40L and the cytokines they secrete that licenses DCs and influences the effector class of the immune response.
Current protocols in immunology | 2016
Karen Laky; Ada M. Kruisbeek
In vivo depletion of T lymphocytes is a means of studying the role of specific T cell populations during defined phases of in vivo immune responses. In this unit, a protocol is provided for injecting monoclonal antibodies (mAbs) into wild‐type adult mice. Depletion of the appropriate subset of cells is verified by flow cytometry analysis of lymph node and spleen cell suspensions in pilot experiments. Once conditions have been established, depleted mice can be used to study the impact of T cell subsets on a variety of in vivo immune responses. The depleted condition may be maintained by repeated injections of the monoclonal antibody, or reversed by normal thymopoiesis following discontinuation of antibody administration.
Current Opinion in Immunology | 2005
Karen Laky; B. J. Fowlkes
Journal of Leukocyte Biology | 2018
Caroline M. Percopo; Julia O. Krumholz; Elizabeth R. Fischer; Laura S. Kraemer; Michelle Ma; Karen Laky; Helene F. Rosenberg