Pamela Schwartzberg, M.D., Ph.D.
Pamela L. Schwartzberg received her B.A. from Princeton University and her M.D. and Ph.D. degrees from the Columbia College of Physicians and Surgeons, Columbia University. During her Ph.D. studies, she worked with Stephen Goff, Ph.D., Columbia University, on studies of retroviral replication and on early studies using homologous recombination to introduce mutations into the germline of mice - work that helped open a new era in mouse genetics. After an internship at Boston Children's Hospital, she did a fellowship with Harold Varmus, M.D., at the National Cancer Institute, working on signaling pathways involving tyrosine kinases as a special fellow of the Leukemia and Lymphoma Society (in collaboration with Michael Lenardo, M.D., National Institute of Allergy and Infectious Diseases).
She started her own laboratory at the National Human Genome Research Institute at the end of 1997 and was promoted to senior investigator with tenure in 2003. Her laboratory's work has centered on the use of genetic, biochemical and cellular studies to understand T cell signaling, with a focus on pathways affected by primary immunodeficiencies. Dr. Schwartzberg is an adjunct faculty member at the University of Pennsylvania and the George Washington University School of Biomedical Sciences and has received several mentoring awards at NIH. She has served on numerous reviewing and editorial boards and is the recipient of a Searle Scholar's Award, the American Association of Immunologists BD-Pharmingen Biosciences Award for Early Career Scientists and has been elected to the American Society for Clinical Investigation (ASCI) and the Association of American Physicians (AAP).
The ability to successfully fight infection requires the coordinated activation of lymphocytes through their cell-surface antigen receptors: surface immunoglobulins (Ig) on B cells, and T cell receptors (TCR) on T cells. Together with costimulatory molecules, these receptors initiate signal transduction pathways that orchestrate cellular changes and transcriptional networks required for lymphocyte differentiation and function. Understanding these signaling pathways is critical for understanding how hosts respond to pathogens and other immune challenges, such as vaccination.
Studies of human genetic primary immunodeficiencies, as well as mutant mice and cell lines, have demonstrated that pathways regulated by tyrosine phosphorylation are essential for proper lymphocyte activation. Work in the Schwartzberg laboratory focuses on understanding functions of the components of these signaling pathways, in order to help us both understand phenotypes of genetic diseases involving these pathways and to elucidate basic mechanisms of immune responses. To this end, the Schwartzberg group has been studying T cell signaling molecules affected by primary immunodeficiencies, including the Tec family kinase Itk, which functions downstream of the TCR, and the adaptor protein SAP, which functions downstream of the SLAM family of costimulatory/immunomodulatory receptors. They have also integrated this work with studies of related signaling molecules involved in T cell activation, including Phosphatidylinositide Kinase-delta and the Wiskott-Aldrich Syndrome Protein (WASP), mutations of which lead to other primary immunodeficiencies with T cell dysfunction, and components of the mTOR activation pathway that are affected by these genetic defects. While its work focuses on these molecules, the Schwartzberg group's overarching goal is to understand the fundamental processes by which lymphocytes mount effective responses to infection and immunization and to translate these findings to potential therapeutic approaches to a broad range of diseases with immune contributions.
Dr. Schwarztberg's laboratory uses the mouse as its primary genetic organism, due to the strength of genetic approaches and the availability of powerful reagents for examining lymphocyte responses to infection and immunization. However, the group has also expanded into human immunology, through the study both of cells from patients with primary immunodeficiencies and of responses to immunization in humans (as part of studies with the NIH Center for Human Immunology). Together, these integrated studies are providing windows into the mechanistic workings of lymphocytes in the immune system.
- Tec Kinases: Through the generation of mice deficient in Rlk and Itk, Dr. Schwartzberg's lab has shown that Itk is a critical modulator of TCR signaling, required for full activation of PLC-γ, Ca2+ mobilization and ERK activation, as well as for regulating the actin cytoskeleton reorganization that T cells undergo upon interaction with target cells. They have recently uncovered roles for Itk in regulating inositol phosphate signaling, mTOR activation and cellular metabolism. Nonetheless, mutations affecting Itk do not eliminate TCR signaling, but rather modulate it, giving rise to altered T cell populations and altered T cell cytokine production and functional responses. This work has further lead to insight on how TCR signals help integrate with other signaling pathways, to determine types of cytokines produced by CD4 T helper cells and the balance of differentiation of effector cells versus regulatory cells. The importance of Itk in T cell function is highlighted by recent reports showing Itk is mutated in a primary immunodeficiency associated with recurrent infections and fulminant responses to Epstein-Barr Virus (EBV). Dr. Schwartzberg's current work focuses on the roles of Itk in regulating distinct types of cytokine responses, its functions during T cell development and the regulation of innate T lymphocyte populations, as well as its role in regulating CD8 T cell cytotoxicity.
- SAP and XLP: X-linked lymphoproliferative Disease (XLP) is another rare genetic disease associated with fatal responses to EBV, lymphoproliferation and abnormal antibody responses. The majority of cases of XLP are caused by mutations affecting a small adaptor molecule, SAP that binds to members of the SLAM family of costimulatory receptors. Through the generation and study of a mouse model, the Schwartzberg group has helped uncover additional features of XLP, including an inability to form germinal centers, the site of generation of high affinity antibodies and long-lived humoral immunity, and a lack of invariant NKT and other "innate" T cell populations. They have further shown that SAP and the associated SLAM family members are required for proper T:B cell interactions. Thus, in the absence of SAP, T cells cannot adhere properly to B cells and thus, cannot provide help to B cells to generate germinal centers, nor efficiently kill B cells, which are infected by EBV. They showed that these defects were secondary to inhibitory signaling from the SLAM family members Ly108 and 2B4 in the absence of SAP, resulting from recruitment of the SHP-1 phosphatase and thereby preventing proper T cell activation and formation of the T:B cell immune synapse. The Schwartzberg lab's data have provided insight into the diverse phenotypes of XLP, by demonstrating that they arise from altered T:B cell interactions in the absence of SAP, suggesting potential therapeutic intervention via inhibition of SLAM family interactions.
Studies of CD8+ T cell function have now been extended to additional primary immunodeficiencies, including those resulting from Itk-deficiency or activating mutations of PI3K p110delta, both of which also show an inability to clear EBV, associated in some cases with increased predisposition to lymphoma. Through the generation of mouse models and the study of patient cells, the Schwartzberg group is studying the effects on CD8 cell cytolysis of different targets to understand mechanisms behind the phenotypes of these diseases.
Finally, the group has continued its research on the regulation of germinal center formation through studies of SAP and the regulation of follicular T helper cells, the critical CD4+ T cell population that provides help for germinal center formation and the generation of long-term humoral immunity. This work has been complemented by studies of immunization and determinants of successful antibody responses as part of collaborative studies with the NIH Center for Human Immunology.
Schwartzberg PL, Goff SP, Robertson EJ. Germline Transmission of a Mutation in c-abl introduced by homologous recombination in Murine Embryonic Stem Cells. Science, 246:799-803. 1989. [PubMed]
Debnath J., Chamorro M., Czar MJ, Schaeffer EM, Lenardo MJ, Varmus HE, Schwartzberg PL. rlk/TXK encodes two forms of a novel cysteine string tyrosine kinase activated by Src family kinases. Mol Cell Biol, 19(2):1498-507. 1999. [PubMed]
Schaeffer EM, Debnath J, Yap G, McVicar D, Liao XC, Littman DR, Sher A, Varmus HE, Lenardo MJ, Schwartzberg PL. Requirement for Tec kinases Rlk and Itk in T cell receptor signaling and immunity. Science, 284(5414):638-41. 1999. [PubMed]
Sun Z, Arendt C, Ellmeirer W, Schaeffer E, Sunshine M, Annes J, Petrzilka Kupfer A, Schwartzberg PL, Littman D. PKC-theta is required for TCR-induced NF-kappaB activation in mature but not immature T lymphocytes. Nature, 404:402-407. 2002. [PubMed]
Schaeffer E, Broussard C, Debnath J, Anderson S, McVicar D, Schwartzberg P. Tec family kinases modulate thresholds for thymocyte development and selection. J Exp Med, 192:987-1000. 2000. [PubMed]
Czar MJ, Kersh EN, Mijares LA, Lanier G, Lewis J, Yap G, Chen A, Sher A, Duckett CS, Ahmed R, Schwartzberg PL. Altered lymphocyte responses and cytokine production in mice deficient in the X-linked lymphoproliferative disease gene SH2D1A/DSHP/SAP. Proc Natl Acad Sci U S A, 98:7449-54. 2001. [PubMed]
Schaeffer EM, Yap GS, Lewis CM, Czar MJ, McVicar DW, Cheever AW, Sher A, Schwartzberg PL. Mutation of Tec family kinases alters T helper cell differentiation. Nat Immunol, 2:1183-8. 2001. [PubMed]
Crotty S, Kersh EN, Cannons J, Schwartzberg PL, Ahmed R. SAP is required for generating long-term humoral immunity. Nature, 16;421(6920):282-7. 2003. [PubMed]
Takesono A, Horai, R, Mandai M, Dombroski D, Schwartzberg, PL. Requirement for Tec family kinases in chemokine-induced migration and activation of Cdc42 and Rac. Curr. Biol, 10:917-22. 2004. [PubMed]
Finkelstein L.D., Schwartzberg P.L. Tec kinases: shaping T-cell activation through actin. Trends Cell Biol, 14:443-451. 2004. [PubMed]
Cannons JL, Hill, B. Yu, L.J., Mijares, L.A., Dombroski, D., Nichols, K.E., Antonellis, A., Koretzky, G., Gardner, K., and Schwartzberg, P.L. SAP Regulates T(H)2 Differentiation and PKC-theta;-Mediated Activation of NF-kappaB1. Immunity, 21:693-706. 2004. [Full Text]
Broussard, C, Fleishaker, C, Horai, R, Chetana, M, Lewis, CM, Venegas, AM, Sharp, L, Hedrick, S, Fowlkes, BJ and Schwartzberg, PL. Altered development of CD8+ T cell lineages in mice deficient in the Tec kinases Itk and Rlk. Immunity, 25:93-104. 2006. [PubMed]
Horai R, Mueller KL, Handon RA, Cannons JL, Anderson SM, Kirby MR, Schwartzberg PL. Requirements for selection of conventional and innate T lymphocyte lineages. Immunity, 27(5):775-85. 2007. [PubMed]
Readinger JA, Schiralli GM, Jiang JK, Thomas CJ, August A, Henderson AJ, Schwartzberg PL. Selective targeting of ITK blocks multiple steps of HIV replication. Proc Natl Acad Sci U S A, 105(18):6684-9. 2008. [PubMed]
Qi H, Cannons JL, Klauschen F, Schwartzberg PL, Germain RN. SAP-controlled T-B cell interactions underlie germinal centre formation. Nature, 455(7214):764-9. 2008. [PubMed]
Gomez-Rodriguez J, Sahu N, Handon R, Davidson, T, Anderson SM, Kirby MR, August A, Schwartzberg PL. Differential expression of IL-17A and IL-17F is coupled to TCR signaling via Itk-mediated regulation of NFATc1. Immunity, 31(4):587-97. 2009. [PubMed]
Cannons J, Qi H, Lu KT, Ghai M, Gomez-Rodriguez J, Cheng J, Wakeland EK, Germain RN, and Schwartzberg PL. Optimal germinal center responses require a multi-stage T:B cell adhesion process involving integrins, SLAM-associated protein and CD84. Immunity, 32:253-65. 2010. [PubMed Central]
Lu KT, Kanno Y, Cannons JL, Handon R, Elkahloun A, Anderson SM, Wei L, Sun H, O'Shea JJ, and Schwartzberg PL. Functional and epigenetic studies reveal multistep differentiation and plasticity of follicular T helper cells. Immunity, 35:622-32. 2011. [PubMed Central]
Zhao, F, Cannons JL, Dutta M, Griffiths GM, and Schwartzberg PL. Positive and Negative Signaling through SLAM receptors regulate Synapse Organization and Thresholds of Cytolysis. Immunity, 36:1003-16. 2012. [PubMed]
Lucas CL, Kuehn HS, Zhao F, Niemela JE, Deenick EK, Palendira U, Avery DT, Moens L, Cannons JL, Biancalana M, Stoddard J, Ouyang W, Frucht DM, Rao VK, Atkinson TP, Agharahimi A, Hussey AA, Folio LR, Olivier KN, Fleisher TA, Pittaluga S, Holland SM, Cohen JI, Oliveira JB, Tangye SG, Schwartzberg PL, Lenardo MJ, Uzel G. Dominant-activating germline mutations in the gene encoding the PI(3)K catalytic subunit p110? result in T cell senescence and human immunodeficiency. Nat Immunol, 15:88-97. 2014. [PubMed]
Gomez-Rodriguez J, Wohlfert EA, Handon R, Meylan F, Wu, JZ, Anderson SM, Kirby MR, Belkaid Y and Schwartzberg PL. Itk-mediated integration of T Cell Receptor and Cytokine signaling regulates the balance between Th17 and regulatory T cells. J Exp Med, 211:529-43. 2014. [PubMed]
Tsang J, Schwartzberg PL, Kotliatov Y, Biancotta A, Xhi Z, Germain RL, Wang E, Olnes MJ, Narayanan M, Golding H, Moir S, Dickler HB, Perl S, Cheung F, Baylor HIPC Center and The CHI Consortium. Global analyses of human immune variation reveal baseline predictors of post-vaccination responses. Cell, 157:499-513. 2014. [PubMed]
Wu T, Shin HM, Moseman EA, Ji Y, Huang B, Harly C, Sen JM, Berg LJ, Gattinoni L, McGavern DB, Schwartzberg PL. TCF1 Is Required for the T Follicular Helper Cell Response to Viral Infection. Cell Rep, 12(12):2099-110. 2015. [PubMed]
Last updated: March 15, 2018