T-cell activation and receptor downmodulation precede deletion induced by mucosally administered antigen
Jacqueline M. Benson, … , Thomas Forsthuber, Caroline C. Whitacre
Jacqueline M. Benson, … , Thomas Forsthuber, Caroline C. Whitacre
Published October 15, 2000
Citation Information: J Clin Invest. 2000;106(8):1031-1038. https://doi.org/10.1172/JCI10738.
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Article

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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T-cell activation occurs early, and later it declines after MBP feeding....
T-cell activation occurs early, and later it declines after MBP feeding. (a) MBP TCR Tg mice were fed vehicle or 100 mg MBP and sacrificed 1 or 3 days after feeding. Peripheral LNs were harvested from three animals per group, and pooled single-cell suspensions were analyzed by flow cytometry for early activation antigen (CD69) expression within Vβ8+/CD4+ Tg populations. (b–d) Adult MBP TCR Tg mice were thymectomized, then fed vehicle or 100 mg MBP, and sacrificed on days 1, 3, and 14 after feeding. TGF-β production was measured by ELISA from supernatants of splenocytes cultured with MBP. TGF-β concentration (pg/ml) was determined from a standard curve for duplicate cultures from individual animals, and the mean for each group ± SEM is shown (n = 2–4). Values were not statistically different from vehicle-fed control mice. IL-2, IFN-γ, IL-5, and IL-4 production was measured by ELISPOT from LN cells cultured with MBP. There was negligible production of any cytokine without in vitro restimulation with MBP. Responding cells per million were determined for replicate wells from individual animals, and the mean for each group ± SEM is shown (n = 2–6). AValues are statistically different from vehicle-fed mice at P ≤ 0.05.