Skip to main content
eScholarship
Open Access Publications from the University of California

UCSF

UC San Francisco Electronic Theses and Dissertations bannerUCSF

The Regulation and Mechanism of Lymphocyte Egress

  • Author(s): Shiow, Lawrence Raymond
  • Advisor(s): Cyster, Jason G
  • et al.
Abstract

Lymphocyte and thymocyte egress are poorly understood processes that are required for proper immune function. In the periphery, naïve lymphocytes must egress from secondary lymphoid organs to recirculate and travel to other tissues. From the thymus, mature thymocytes must egress to populate the T cell compartment that surveys the periphery. The G-protein coupled receptor (GPCR) sphingosine-1-phosphate receptor-1 (S1P1) is intrinsically required for both egress steps, but how S1P1 promotes egress remains unclear.

First, we studied the role of the early activation antigen CD69 during lymph node "shutdown," a transient block in lymphocyte egress triggered by various innate immune stimuli, including type I interferons (IFN-α/β). We found that CD69 interacts with and negatively regulates S1P1, acting downstream of IFN-α/β to promote lymphocyte retention in lymphoid organs. Our study is the first to describe a trafficking function for CD69 and to report an interaction between a C-type lectin and a GPCR.

Next, we studied a spontaneous thymic egress mutant strain carrying the recessive ptcd (peripheral T cell deficiency) locus. We found that ptcd mice have an intrinsic T cell migration and trafficking defect, and carry a point mutation in the actin regulator Coronin-1A. This mutation causes protein mislocalization and enhanced Arp2/3 inhibition. Our findings contributed new insight to the mechanism of Arp2/3 regulation by Coronin-1A during T cell trafficking, and also prompted us to identify an atypical human T-B+NK+ SCID patient with Coronin-1A deficiency.

Together, these studies contribute to our understanding of the regulation and mechanism of lymphocyte egress. Furthermore, we've provided a mechanism for the lymph node shutdown phenomenon, discovered a novel lectin-GPCR interaction, provided new insight into actin biology, and reported a novel genetic defect in a patient with T-B+NK+ severe combined immunodeficiency.

Main Content
Current View