Pamela L. Schwartzberg, M.D., Ph.D.

Chief & Senior Investigator, Genetic Disease Research Branch
Head, Cell Signaling and Immunity Section

Scientific Summary

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.

Cytotoxic T lymphocytes (CTLs) interacting with target cells. Green: Actin; Red: Labeled Target Cell; White: Granzyme B Left shows a CTL where cytotoxic granules are not polarized. Right shows a CTL with polarized granules about to kill a target cell.

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.

Specific projects:

  • 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.

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Posted: January 6, 2015