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CD28/CTLA-4/B7 costimulatory pathway blockade affects regulatory T-cell function in autoimmunity

Significance statement

Since costimulation is crucial for T-cell activation, the effects of blocking costimulatory interactions with the purpose of interfering with inappropriate or unwanted T-cell actions (e.g. in autoimmunity or after transplantation) have been exploited extensively. The CTLA-4Ig fusion protein (which blocks CD28/B7 costimulation), for example, is in clinical use for the treatment of rheumatoid arthritis (Abatacept) since 2005. Furthermore, a second generation molecule (Belatacept) has been approved for the treatment of rejection of renal transplants in 2011. Despite its success, the precise mechanisms underlying its efficacy are not completely understood. Recently, some concerns have been raised that the effect of CTLA-4Ig on the immune system is more complex and not limited to blocking T-cell activation. In particular, CTLA-4Ig might interfere with the activity of regulatory T cells, which are themselves also operative in suppressing unwanted T-cell activation. In this article, we report our findings that CTLA-4Ig treatment exacerbates autoimmunity of the central nervous system (CNS) in an animal model when given after T-cell priming has already started. Indeed, this disease exacerbation was due to interference at a critical time point with expansion and activation of regulatory T cells. A particular treatment regime, which is effective in one disease or setting thus might not work or even be dangerous in another. Most importantly, timing of the treatment seems to be crucial for the outcome of the therapy, as there apparently is a delay between priming of effector versus regulatory cells. Although blocking costimulation is a very promising strategy to treat inappropriate T-cell activation, we should be aware that it might have complex effects. An ideal therapy would consequently need to find a balance between maximal T effector cell-suppression and minimal interference with regulatory T cells. The findings stress the importance of further deciphering the mechanisms underlying tolerance induction by costimulation blockade.

Figure Legend 

The potential effects of CTLA-4Ig treatment on Treg cells. Naïve T cells need two distinct signals in order to get fully activated. The first signal is transmitted through the T-cell receptor (TCR), which recognizes an antigen presented by specialized antigen presenting cells (APCs) on major histocompatibility complex (MHC) molecules. In addition, a second non-specific signal is provided by the ligation of the costimulatory molecule CD28, which binds the two ligands B7-1 (CD80) and B7-2 (CD86). The fusion protein CTLA-4Ig, which is used to treat inappropriate T-cell activation, engages both B7 ligands and therefore blocks CD28 mediated activation. However, CTLA-4Ig treatment does not only prevent the activation of potentially harmful effector T-cells. It can also interfere with the activation and function of regulatory T (Treg) cells. CTLA-4Ig treatment can directly affect Treg-cell activation by inhibiting CD28 signalling (A). Furthermore, it can prevent the ligation of the B7 ligands to CTLA-4. CTLA-4 is constitutively expressed on Treg cells and it is crucial for Treg-cell function. Therefore, CTLA-4Ig can also interfere with the CTLA-4 mediated suppressive function of Treg cells (B).

CD28/CTLA-4/B7 costimulatory pathway blockade affects regulatory T-cell function in autoimmunity. Global Medical Discovery

 

 

 

 

 

 

 

 

 

 

 

 

Journal Reference

Vogel I, Kasran A, Cremer J, Kim YJ, Boon L, Van Gool SW, Ceuppens JL. Eur J Immunol. 2015 Feb 27.

Laboratory of Clinical Immunology, KU Leuven, University Hospital Gasthuisberg, Leuven, Belgium.

Abstract

Naïve T cells require B7/CD28 costimulation in order to be fully activated. Attempts to block this pathway have been effective in preventing unwanted immune reactions. As B7 blockade might also affect Treg cells and interfere with negative signaling through membrane CTLA-4 on effector T (Teff) cells, its immune-modulatory effects are potentially more complex. Here, we used the mouse model of multiple sclerosis (MS), EAE, to study the effect of B7 blockade. An effective therapy for MS patients has to interfere with ongoing inflammation, and therefore we injected CTLA-4Ig at day 7 and 9 after immunization, when myelin-reactive T cells have been primed and start migrating toward the CNS. Surprisingly, B7 blockade exacerbated disease signs and resulted in more severe CNS inflammation and demyelination, and was associated with an enhanced production of the inflammatory cytokines IL-17 and IFN-γ. Importantly, CTLA-4Ig treatment resulted in a transient reduction of Ki67 and CTLA-4 expression and function of peripheral Treg cells. Taken together, B7 blockade at a particular stage of the autoimmune response can result in the suppression of Treg cells, leading to a more severe disease.

© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

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