Impaired Trafficking of Gnai2+/− and Gnai2−/− T Lymphocytes: Implications for T Cell Movement within Lymph Nodes

Sphingosine-1-phosphate (S1P) receptor 1 (S1PR1) is critical for lymphocyte egress from lymphoid organs. Lymphocytes encounter low S1P concentrations near exit sites before transmigration, yet S1PR1 signaling is rapidly terminated after exposure to S1P. How lymphocytes maintain S1PR1 signaling in a low S1P environment near egress sites is unknown. Here we identify dynamin 2, an essential component of endocytosis, as a novel regulator of T cell egress. Mice with T cell–specific dynamin 2 deficiency had profound lymphopenia and impaired egress from lymphoid organs. Dynamin 2 deficiency caused impaired egress through regulation of S1PR1 signaling, and transgenic S1PR1 overexpression rescued egress in dynamin 2 knockout mice. In low S1P concentrations, dynamin 2 was essential for S1PR1 internalization, which enabled continuous S1PR1 signaling and promoted egress from both thymus and lymph nodes. In contrast, dynamin 2–deficient cells were only capable of a pulse of S1PR1 signaling, which was insufficient for egress. Our results suggest a possible mechanism by which T lymphocytes positioned at exit portals sense low S1P concentrations, promoting their egress into circulatory fluids.

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The Reduced Expression of 6ckine in the plt Mouse Results from the Deletion of One of Two 6ckine Genes

Journal of Experimental Medicine ◽

10.1084/jem.190.8.1183 ◽

1999 ◽

Vol 190 (8) ◽

pp. 1183-1188 ◽

Cited By ~ 160

Author(s):

Galya Vassileva ◽

Hortensia Soto ◽

Albert Zlotnik ◽

Hideki Nakano ◽

Terutaka Kakiuchi ◽

...

Keyword(s):

T Cells ◽

Lymph Node ◽

T Cell ◽

T Lymphocytes ◽

Lymph Nodes ◽

Lymphoid Organs ◽

Peyer's Patches ◽

White Pulp ◽

Naive T Lymphocytes

6Ckine is an unusual chemokine capable of attracting naive T lymphocytes in vitro. It has been recently reported that lack of 6Ckine expression in lymphoid organs is a prominent characteristic of mice homozygous for the paucity of lymph node T cell (plt) mutation. These mice show reduced numbers of T cells in lymph nodes, Peyer's patches, and the white pulp of the spleen. The genetic reason for the lack of 6Ckine expression in the plt mouse, however, has remained unknown. Here we demonstrate that mouse 6Ckine is encoded by two genes, one of which is expressed in lymphoid organs and is deleted in plt mice. A second 6Ckine gene is intact and expressed in the plt mouse.

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Gastrointestinal T Lymphocytes Retain High Potential for Cytokine Responses but Have Severe CD4+ T-Cell Depletion at All Stages of Simian Immunodeficiency Virus Infection Compared to Peripheral Lymphocytes

Journal of Virology ◽

10.1128/jvi.72.8.6646-6656.1998 ◽

1998 ◽

Vol 72 (8) ◽

pp. 6646-6656 ◽

Cited By ~ 150

Author(s):

Zeljka Smit-McBride ◽

Joseph J. Mattapallil ◽

Michael McChesney ◽

David Ferrick ◽

Satya Dandekar

Keyword(s):

T Cells ◽

T Cell ◽

T Lymphocytes ◽

Lymph Nodes ◽

Cell Depletion ◽

T Cell Depletion ◽

Cytokine Responses ◽

Immunodeficiency Virus ◽

Siv Infection ◽

Ifn Γ

ABSTRACT Gastrointestinal complications in human immunodeficiency virus (HIV) infection are indicative of impaired intestinal mucosal immune system. We used simian immunodeficiency virus (SIV)-infected rhesus macaques as an animal model for HIV to determine pathogenic effects of SIV on intestinal T lymphocytes. Intestinal CD4+ T-cell depletion and the potential for cytokine responses were examined during SIV infection and compared with results for lymphocytes from lymph nodes and blood. Flow cytometric analysis demonstrated severe depletion of CD4+CD8− single-positive T cells and CD4+CD8+ double-positive T cells in intestinal lamina propria lymphocytes (LPL) and intraepithelial lymphocytes (IEL) during primary SIV infection which persisted through the entire course of SIV infection. In contrast, CD4+ T-cell depletion was gradual in peripheral lymph nodes and blood. Flow cytometric analysis of intracellular gamma interferon (IFN-γ) and interleukin-4 (IL-4) production following short-term mitogenic activation revealed that LPL retained same or higher capacity for IFN-γ production in all stages of SIV infection compared to uninfected controls, whereas peripheral blood mononuclear cells displayed a gradual decline. The CD8+ T cells were the major producers of IFN-γ. There was no detectable change in the frequency of IL-4-producing cells in both LPL and peripheral blood mononuclear cells. Thus, severe depletion of CD4+ LPL and IEL in primary SIV infection accompanied by altered cytokine responses may reflect altered T-cell homeostasis in intestinal mucosa. This could be a mechanism of SIV-associated enteropathy and viral pathogenesis. Dynamic changes in intestinal T lymphocytes were not adequately represented in peripheral lymph nodes or blood.

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