T cell function and expression are dramatically altered in T cell receptor Vγ1.1Jγ4Cγ4 transgenic mice

Abstract T-cell receptor (TCR) triggering by antigens activates a sophisticated intracellular signaling network leading to transcriptional activation, proliferation and differentiation of T cells. These events ultimately culminate in adaptive immune responses. Over recent years it has become evident that reactive oxygen species (ROS) play an important role in T-cell activation. It is now clear that ROS are involved in the regulation of T-cell mediated physiological and pathological processes. Upon TCR triggering, T cells produce oxidants, which originate from different cellular sources. In addition, within inflamed tissues, T cells are exposed to exocrine ROS produced by activated phagocytes or other ROS-producing cells. Oxidative modifications can have different effects on T-cell function. Indeed, they can stimulate T-cell activation but they can be also detrimental. These opposite effects of oxidation likely depend on different factors such as ROS concentration and source and also on the differentiation status of the T cells. Despite the well-stablished fact that ROS represent important modulators of T-cell activation, the precise molecular mechanisms of their action are far from clear. Here, we summarize the present knowledge on redox regulation of T-cell function with a particular emphasis on the redox regulation of TCR signaling.

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Regulation of the Small GTPase Rap1 and Extracellular Signal-Regulated Kinases by the Costimulatory Molecule CTLA-4

Molecular and Cellular Biology ◽

10.1128/mcb.25.10.4117-4128.2005 ◽

2005 ◽

Vol 25 (10) ◽

pp. 4117-4128 ◽

Cited By ~ 39

Author(s):

Tara J. Dillon ◽

Kendall D. Carey ◽

Scott A. Wetzel ◽

David C. Parker ◽

Philip J. S. Stork

Keyword(s):

T Cells ◽

T Cell ◽

Transgenic Mice ◽

Cell Function ◽

Costimulatory Molecule ◽

Interleukin 2 ◽

Cell Receptor ◽

Small Gtpase ◽

Mitogen Activated Protein Kinase ◽

T Cell Function

ABSTRACT The mitogen-activated protein kinase extracellular signal-regulated kinase (ERK) is activated following engagement of the T-cell receptor and is required for interleukin 2 (IL-2) production and T-cell proliferation. This activation is enhanced by stimulation of the coreceptor CD28 and inhibited by the coreceptor CTLA-4. We show that the small G protein Rap1 is regulated in the opposite manner; it is inhibited by CD28 and activated by CTLA-4. Together, CD3 and CTLA-4 activate Rap1 in a sustained manner. To delineate T-cell function in the absence of Rap1 activity, we generated transgenic mice expressing Rap1GAP1, a Rap1-specific GTPase-activating protein. Transgenic mice showed lymphadenopathy, and transgenic T cells displayed increased ERK activation, proliferation, and IL-2 production. More significantly, the inhibitory effect of CTLA-4 on T-cell function in Rap1GAP1-transgenic T cells was reduced. We demonstrate that CTLA-4 activates Rap1, and we propose that intracellular signals from CTLA-4 antagonize CD28, at least in part, at the level of Rap1.

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