Lymphocyte Activation Gene-3 (CD223) Regulates the Size of the Expanding T Cell Population Following Antigen Activation In Vivo

ABSTRACT Dendritic cells, particularly those residing in the spleen, are thought to orchestrate acquired immunity to malaria, but it is not known how the splenic dendritic cell population responds to malaria infection and how this response compares with the responses of other antigen-presenting cells. We investigated this question for Plasmodium chabaudi AS infection in C57BL/6 mice. We found that dendritic cells, defined here by the CD11c marker, migrated from the marginal zone of the spleen into the CD4+ T-cell area within 5 days after parasites entered the bloodstream. This contrasted with the results observed for the macrophage and B-cell populations, which expanded greatly but did not show any comparable migration. Over the same time period dendritic cells showed upregulation of CD40, CD54, and CD86 costimulatory molecules that are required for successful T-cell activation. In dendritic cells, the peak intracellular gamma interferon expression (as shown by fluorescence-activated cell sorting) was on day 5, 2 days earlier than the peak expression in B-cells or macrophages. These findings show that splenic dendritic cells are actively engaged in the earliest phase of malarial infection in vivo and are likely to be critical in shaping the subsequent immune response.

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Aplp1 and the Aplp1-Lag3 Complex facilitates transmission of pathologic alpha-synuclein

10.1101/2021.05.01.442157 ◽

2021 ◽

Author(s):

Xiaobo Mao ◽

Hao Gu ◽

Donghoon Kim ◽

Yasuyoshi Kimura ◽

Ning Wang ◽

...

Keyword(s):

Parkinson Disease ◽

Molecular Mechanism ◽

Amyloid Beta ◽

Dopaminergic Neurons ◽

Lymphocyte Activation ◽

Alpha Synuclein ◽

Therapeutic Strategies ◽

Behavioral Deficits ◽

Lymphocyte Activation Gene

Pathologic alpha-synuclein (alpha-syn) spreads from cell-to-cell, in part, through binding to the lymphocyte-activation gene 3 (Lag3). Here we report that amyloid beta precursor-like protein 1 (Aplp1) forms a complex with Lag3 that facilitates the binding, internalization, transmission, and toxicity of pathologic alpha-syn. Deletion of both Aplp1 and Lag3 eliminates the loss of dopaminergic neurons and the accompanying behavioral deficits induced by alpha-syn preformed fibrils (PFF). Anti-Lag3 prevents the internalization of alpha-syn PFF by disrupting the interaction of Aplp1 and Lag3, and blocks the neurodegeneration induced by alpha-syn PFF in vivo. The identification of Aplp1 and the interplay with Lag3 for alpha-syn PFF induced pathology advances our understanding of the molecular mechanism of cell-to-cell transmission of pathologic alpha-syn and provides additional targets for therapeutic strategies aimed at preventing neurodegeneration in Parkinson disease and related alpha-synucleinopathies.

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Biochemical Analysis of the Regulatory T Cell Protein Lymphocyte Activation Gene-3 (LAG-3; CD223)

The Journal of Immunology ◽

10.4049/jimmunol.173.11.6806 ◽

2004 ◽

Vol 173 (11) ◽

pp. 6806-6812 ◽

Cited By ~ 54

Author(s):

Nianyu Li ◽

Creg J. Workman ◽

Stefani M. Martin ◽

Dario A. A. Vignali

Keyword(s):

T Cell ◽

Regulatory T Cell ◽

Biochemical Analysis ◽

Lymphocyte Activation ◽

Cell Protein ◽

Lymphocyte Activation Gene

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Soluble CD30 and Lymphocyte Activation Gene-3 (CD223), as Potential Serological Markers of T Helper-Type Cytokine Response Induced by Acellular Pertussis Vaccine

International Journal of Immunopathology and Pharmacology ◽

10.1177/205873920601900109 ◽

2006 ◽

Vol 19 (1) ◽

pp. 205873920601900 ◽

Cited By ~ 6

Author(s):

C. M. Ausiello ◽

R. Palazzo ◽

F. Spensieri ◽

F. Urbani ◽

M. Massari ◽

...

Keyword(s):

T Cell ◽

Pertussis Vaccine ◽

Lymphocyte Activation ◽

T Cell Responses ◽

Serological Markers ◽

T Helper ◽

Cell Responses ◽

Soluble Cd30 ◽

Vaccine Antigens ◽

Lymphocyte Activation Gene

T cell responses are involved in vaccine-induced immunity to pertussis but no easy-to-monitor, serological markers are available to assess these responses. The lymphocyte activation gene-3 (CD223) molecule is present on, and released by, activated T helper (Th) 1 cells, whereas CD30 molecules have been associated with Th2 immune responses. Starting from the recent knowledge of the cytokine profile induced by pertussis vaccination, we examined the levels of soluble (s)CD223 and sCD30 proteins in child recipients of acellular pertussis (aP) and diphtheria-tetanus (DT) vaccines and in children receiving DT vaccine only, as control. The correlation of the two proteins with specific antibody and T cell responses was assessed. The main findings are: i) sCD223 and sCD30 levels are inversely related, suggesting that the two markers are the expression of different and counter-regulated T-cell responses; ii) sCD30 level correlated with induction of T cell proliferation to pertussis vaccine antigens and antibody response to pertussis toxin. Overall, sCD30 and sCD223 levels seem to be promising candidate markers to assess the induction of Th-type responses in vaccine recipients.

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Structural and functional studies of the early T lymphocyte activation 1 (Eta-1) gene. Definition of a novel T cell-dependent response associated with genetic resistance to bacterial infection.

Journal of Experimental Medicine ◽

10.1084/jem.170.1.145 ◽

1989 ◽

Vol 170 (1) ◽

pp. 145-161 ◽

Cited By ~ 215

Author(s):

R Patarca ◽

G J Freeman ◽

R P Singh ◽

F Y Wei ◽

T Durfee ◽

...

Keyword(s):

T Cell ◽

Bacterial Infection ◽

T Lymphocyte ◽

Inbred Mouse ◽

Genetic Resistance ◽

Lymphocyte Activation ◽

Cellular Adhesion ◽

Mouse Strains ◽

T Lymphocyte Activation

We describe a murine cDNA, designated Early T lymphocyte activation 1 (ETA-1) which is abundantly expressed after activation of T cells. Eta-1 encodes a highly acidic secreted product having structural features of proteins that bind to cellular adhesion receptors. The Eta-1 gene maps to a locus on murine chromosome 5 termed Ric that confers resistance to infection by Rickettsia tsutsugamushi (RT), an obligate intracellular bacterium that is the etiological agent for human scrub typhus. With one exception, inbred mouse strains that expressed the Eta-1a allele were resistant to RT infection (RicR), and inbred strains expressing the Eta-1b allele were susceptible (RicS). These findings suggest that Eta-1 is the gene inferred from previous studies of the Ric locus (5). Genetic resistance to RT infection is associated with a strong Eta-1 response in vivo and inhibition of early bacterial replication. Eta-1 gene expression appears to be part of a surprisingly rapid T cell-dependent response to bacterial infection that may precede classical forms of T cell-dependent immunity.

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Antigen-Responsive CD4+ T Cells from C3H Mice Chronically Infected with Leishmania amazonensis Are Impaired in the Transition to an Effector Phenotype

Infection and Immunity ◽

10.1128/iai.74.3.1547-1554.2006 ◽

2006 ◽

Vol 74 (3) ◽

pp. 1547-1554 ◽

Cited By ~ 18

Author(s):

Amanda E. Ramer ◽

Yannick F. Vanloubbeeck ◽

Douglas E. Jones

Keyword(s):

T Cells ◽

T Cell ◽

Cell Population ◽

T Cell Response ◽

Leishmania Amazonensis ◽

Effector Memory ◽

Intrinsic Defect ◽

Antigen Stimulation ◽

Ifn Γ

ABSTRACT C3HeB/FeJ mice challenged with Leishmania major develop a polarized Th1 response and subsequently heal, whereas Leishmania amazonensis challenge leads to chronic lesions with high parasite loads at 10 weeks postinfection. In this study, a comparison of draining lymph node cells from L. amazonensis- and L. major-infected mice at 10 weeks postinfection showed equivalent percentages of effector/memory phenotype CD44hi CD4+ T cells producing interleukin-2 (IL-2) and proliferating after antigen stimulation. However, these cells isolated from L. amazonensis-infected mice were not skewed toward either a Th1 or Th2 phenotype in vivo, as evidenced by their unbiased Th1/Th2 transcription factor mRNA profile. In vivo antigen stimulation with added IL-12 failed to enhance gamma interferon (IFN-γ) production of CD4+ T cells from L. amazonensis-infected mice. Antigen stimulation of CD4+ T cells from L. amazonensis-infected mice in vitro in the presence of IL-12 resulted in production of only 10 to 15% of the IFN-γ produced by T cells from L. major-infected mice under identical conditions. These results suggest that the CD4+ T-cell response during chronic L. amazonensis infection is limited during the transition from an early activated CD4+ T-cell population to an effector cell population and demonstrate that these T cells have an intrinsic defect beyond the presence or absence of IL-12 during antigen stimulation.

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