The thiol redox state of lymphoid organs is modified by immunization: Role of different immune cell populations

Abstract

Resting T lymphocytes can internalize reduced cysteine (Cys) but not cystine, the oxidized form of the amino acid that predominates extracellularly. In vitro studies have shown that DC provide Cys to T cells during antigen presentation, allowing their activation. Here, we show that increased thiol production is a hallmark of immune response in vivo. Indeed, the thiol content of LN increases dramatically after antigen injection. Non-protein thiols co-distribute with DC and are highly abundant in germinal centers. In agreement, activated but not resting B lymphocytes and macrophages release free thiols. Increased thiol release following activation requires thioredoxin and is paralleled by increased thioredoxin expression. The T zones of LN are consistently less stained, and both resting and activated T cells are unable to release thiols. Interestingly, the cystine/glutamate transporter x c À is absent in resting T lymphocytes but is rapidly induced by TCR triggering in vitro, indicating that the release of T cells from the need of exogenous Cys occurs early after activation. These results indicate that a reducing microenvironment is essential to start the immune response but dispensable for its evolution, and support the emerging concept that extracellular redox is implicated in the control of crucial cellular functions.Key words: Lymphocytes Á Macrophages Á Non-protein thiols Á Redox Á Thioredoxin IntroductionThe free thiol (cysteine, Cys) and the disulfide bonded (cystine, CySS) form of the amino acid Cys exist in an equilibrium defined by redox conditions. In the oxidizing environment of the extracellular space, CySS prevails while Cys is almost absent [1]. Conversely, within the cytosol, Cys is present mainly as a free thiol. Interestingly, T lymphocytes can take up Cys but not CySS [2]. Since Cys is an essential amino acid for T lymphocytes, required for GSH synthesis [3], its reduced form must be made available in the microenvironment of T cells to sustain their activation and proliferation. In addition, pre-B and resting B lymphocytes require exogenous Cys to grow in vitro, but are released from this requirement upon differentiation [4].We have previously shown in vitro that, during antigen presentation, DC increase the uptake of CySS and release Cys, allowing T-cell activation. The intracellular conversion of CySS to Cys requires the activity of the redox-active enzyme, thioredoxin (Trx) [5].Although the interaction of T or B lymphocytes with antigenpulsed APC or mitogens may recapitulate lymphocyte activation in vitro, the generation of an immune response in vivo is the result of a much more complex cellular choreography. In secondary lymphoid organs, distinct subsets of immune cells are strategically [6,7]. GC develop a few days after arrival of the antigen from afferent lymphatic drainage, when antigen-activated B cells move to the center of B-cell follicles in secondary lymphoid organs and proliferate within the follicular DC network [6]. Many of the B cells generated within the GC die in situ and nuc...

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