Abstract |
Progressive quantitative and qualitative decline of CD4(+) T cell responses is one hallmark of HIV-1 infection and likely depends on several factors, including a possible contribution by the HIV-1 envelope glycoprotein gp120, which binds with high affinity to the CD4 receptor. Besides virion-associated and cell-expressed gp120, considerable amounts of soluble gp120 are found in plasma or lymphoid tissue, predominantly in the form of gp120-anti-gp120 immune complexes (ICs). Because the functional consequences of gp120 binding to CD4(+) T cells are controversially discussed, we investigated how gp120 affects TCR-mediated activation of human CD4(+) T cells by agonistic anti-CD3 mAb or by HLA class II-presented peptide Ags. We show that the spatial orientation of gp120-CD4 receptor binding relative to the site of TCR engagement differentially affects TCR signaling efficiency and hence CD4(+) T cell activation. Whereas spatially and temporally linked CD4 and TCR triggering at a defined site promotes CD4(+) T cell activation by exceeding local thresholds for signaling propagation, CD4 receptor engagement by gp120-containing ICs all around the CD4(+) T cell undermine its capacity in supporting proximal TCR signaling. In vitro, gp120 ICs are efficiently captured by CD4(+) T cells and thereby render them hyporesponsive to TCR stimulation. Consistent with these in vitro results we show that CD4(+) T cells isolated from HIV(+) individuals are covered with ICs, which at least partially contain gp120, and suggest that IC binding to CD4 receptors might contribute to the progressive decline of CD4(+) T cell function during HIV-1 infection.
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Authors | Kathrin Zimmermann, Thomas Liechti, Anna Haas, Manuela Rehr, Alexandra Trkola, Huldrych F Günthard, Annette Oxenius |
Journal | Journal of immunology (Baltimore, Md. : 1950)
(J Immunol)
Vol. 194
Issue 2
Pg. 637-49
(Jan 15 2015)
ISSN: 1550-6606 [Electronic] United States |
PMID | 25472996
(Publication Type: Clinical Trial, Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2015 by The American Association of Immunologists, Inc. |
Chemical References |
- CD4 Antigens
- HIV Envelope Protein gp120
- Histocompatibility Antigens Class II
- Receptors, Antigen, T-Cell
- gp120 protein, Human immunodeficiency virus 1
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Topics |
- Antigen Presentation
- CD4 Antigens
(immunology)
- CD4-Positive T-Lymphocytes
(immunology, pathology)
- Female
- HIV Envelope Protein gp120
(immunology)
- HIV Infections
(immunology, pathology)
- HIV-1
(immunology)
- Histocompatibility Antigens Class II
(immunology)
- Humans
- Lymphocyte Activation
- Male
- Receptors, Antigen, T-Cell
(immunology)
- Signal Transduction
(immunology)
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