Activation-Induced Nonresponsiveness: A Th-Dependent Regulatory Checkpoint in the CTL Response

T cell burst size is regulated by the duration of TCR engagement and balanced control of Ag-induced activation, expansion, and apoptosis. We found that galectin-1-deficient CD8 T cells undergo greater cell division in response to TCR stimulation, with fewer dividing cells undergoing apoptosis. TCR-induced ERK signaling was sustained in activated galectin-1-deficient CD8 T cells and antagonized by recombinant galectin-1, indicating galectin-1 modulates TCR feed-forward/feedback loops involved in signal discrimination and procession. Furthermore, recombinant galectin-1 antagonized binding of agonist tetramers to the TCR on activated OT-1 T cells. Finally, galectin-1 produced by activated Ag-specific CD8 T cells negatively regulated burst size and TCR avidity in vivo. Therefore, galectin-1, inducibly expressed by activated CD8 T cells, functions as an autocrine negative regulator of peripheral CD8 T cell TCR binding, signal transduction, and burst size. Together with recent findings demonstrating that gal-1 promotes binding of agonist tetramers to the TCR of OT-1 thymocytes, these studies identify galectin-1 as a tuner of TCR binding, signaling, and functional fate determination that can differentially specify outcome, depending on the developmental and activation stage of the T cell.

Section: Discussionmentioning

confidence: 66%

Section: Discussionmentioning

confidence: 99%

Galectin-1 Tunes TCR Binding and Signal Transduction to Regulate CD8 Burst Size

Liu

Tomassian

Bruhn

et al. 2009

“…This suggests ongoing cytotoxic activity against bone marrow-derived APC expressing the cognate Ag at high levels. In that respect CD8 T cells from NP47F5 mice seem to undergo activation induced nonresponsiveness, which was described as a part of the differentiation program of CD8 T cells (38). However, in contrast to T cells undergoing activation induced nonresponsiveness they do not secrete IFN-␥.…”

Section: Discussionmentioning

confidence: 98%

Chronic Exposure to Low Levels of Antigen in the Periphery Causes Reversible Functional Impairment Correlating with Changes in CD5 Levels in Monoclonal CD8 T Cells

Stamou

Jersey

Carmignac³

et al. 2003

This study describes a double-transgenic model in which monoclonal CD8 F5 T cells are chronically exposed to self Ag (nucleoprotein) in the periphery, but are not affected during thymic development. Chronic exposure of CD8 T cells to their cognate Ag rendered them unable to proliferate or produce cytokines in response to antigenic stimulation in vitro. However, the cells still retained some killer function in vivo and continuously eliminated APC expressing high levels of Ag. In addition, when crossed with mice expressing Ag in the anterior pituitary gland (triple-transgenic mice), F5 T cells migrated to this site and killed growth hormone producing somatotrophs. The anergic state was reversible upon transfer into Ag-free recipients, resulting in full recovery of in vitro responsiveness to Ag. Anergic CD8 T cells express higher levels of CD5, a negative regulator of T cell signaling, whereas after transfer and residence in Ag-free hosts, CD5 levels returned to normal. This suggests that up-regulation of negative T cell regulators in peripheral T cells exposed to chronic stimulation by Ag may prevent full functionality and thus avoid overt autoreactivity.

“…Activated CD4 T cells are the major producers of IL-2, a cytokine important to CD8 T cells for the relief of split anergy (10,11), the maintenance of effector populations (12,13), and the promotion of antitumor immunity (14,15). Although the effects of IL-2 on CD8 T cells are diverse, they are limited to the promotion of proliferation and/or survival and do not include the induction of de novo effector functions.…”

Section: Il-21 Promotes Differentiation Of Naive Cd8 T Cells To a Unimentioning

confidence: 99%

IL-21 Promotes Differentiation of Naive CD8 T Cells to a Unique Effector Phenotype

Casey

Mescher

2007

Self Cite

IL-21, the most recently described member of the common γ-chain cytokine family, is produced by activated CD4 T cells, whereas CD8 T cells express the IL-21 receptor. To investigate a possible role for IL-21 in the priming of naive CD8 T cells, we examined responses of highly purified naive OT-I CD8 T cells to artificial APCs displaying Ag and B7-1 on their surface. We found that IL-21 enhanced OT-I clonal expansion and supported development of cytotoxic effector function. High levels of IL-2 did not support development of effector functions, but IL-2 was required for optimal responses in the presence of IL-21. IL-12 and IFN-α have previously been shown to support naive CD8 T cell differentiation and acquisition of effector functions through a STAT4-dependent mechanism. Here, we show that IL-21 does not require STAT4 to stimulate development of cytolytic activity. Furthermore, IL-21 fails to induce IFN-γ or IL-4 production and can partially block IL-12 induction of IFN-γ production. CD8 T cells that differentiate in response to IL-21 have a distinct surface marker expression pattern and are characterized as CD44high, PD-1low, CD25low, CD134low, and CD137low. Thus, IL-21 can provide a signal required by naive CD8 T cells to differentiate in response to Ag and costimulation, and the resulting effector cells represent a unique effector phenotype with highly effective cytolytic activity, but deficient capacity to secrete IFN-γ.