T-cell activation and receptor downmodulation precede deletion induced by mucosally administered antigen
Jacqueline M. Benson, Kim A. Campbell, Zhen Guan, Ingrid E. Gienapp, Scott S. Stuckman, Thomas Forsthuber, Caroline C. Whitacre
Jacqueline M. Benson, Kim A. Campbell, Zhen Guan, Ingrid E. Gienapp, Scott S. Stuckman, Thomas Forsthuber, Caroline C. Whitacre
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T-cell activation and receptor downmodulation precede deletion induced by mucosally administered antigen

Abstract

The fate of antigen-specific T cells was characterized in myelin basic protein (MBP) T-cell receptor (TCR) transgenic (Tg) mice after oral administration of MBP. Peripheral Th cells are immediately activated in vivo, as indicated by upregulation of CD69 and increased cytokine responses (Th1 and Th2). Concurrently, surface TCR expression diminishes and internal TCR levels increase. When challenged for experimental autoimmune encephalomyelitis during TCR downmodulation, Tg mice are protected from disease. To characterize Th cells at later times after antigen feeding, it was necessary to prevent thymic release of naive Tg cells. Therefore, adult Tg mice were thymectomized before treatment. TCR expression returns in thymectomized Tg mice 3 days after MBP feeding and then ultimately declines in conjunction with MBP-specific proliferation and cytokine responses (Th1-type and Th2-type). The decline correlates with an increase in apoptosis. Collectively, these results demonstrate that a high dose of fed antigen induces early T-cell activation and TCR downmodulation, followed by an intermediate stage of anergy and subsequent deletion.

Authors

Jacqueline M. Benson, Kim A. Campbell, Zhen Guan, Ingrid E. Gienapp, Scott S. Stuckman, Thomas Forsthuber, Caroline C. Whitacre

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A single high dose of orally administered antigen reduces TCR expression...
A single high dose of orally administered antigen reduces TCR expression without affecting lymphoid organ cellularity. (a) MBP TCR Tg mice were fed vehicle or 1 mg MBP every other day for 10 days (five feeds), or vehicle or 5, 25, 50, or 100 mg MBP once. Lymphocytes were analyzed by flow cytometry 1 day after the last feeding for expression of the Tg Vβ8.2 TCR on CD4+ cells. Each bar is the mean percentage of Vβ8+/CD4+ cells ± SEM (n = 3). AValues are statistically different from the corresponding vehicle-fed controls at P ≤ 0.05. (b) Peripheral LN cells from MBP TCR Tg mice fed 100 mg MBP or 100 mg OVA were analyzed by flow cytometry 1 or 3 days after feeding. Each bar is the mean percentage of Vβ8+/CD4+ cells within the lymphocyte population ± SEM (n = 3). AValues are statistically different from OVA-fed control mice at P ≤ 0.05. (c) The total number of cells in single-cell suspensions from spleen (SPL), peripheral lymph nodes (LN), and mesenteric LN (MLN) of MBP- or vehicle-fed Tg mice was determined by trypan blue exclusion 1 or 3 days after feeding. Data are reported as the mean number of cells × 106 ± SEM (n = 3–11). Values were not statistically different from vehicle-fed control mice.