mRNA bulk seq on human T regolatory cells

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Description: Human T regulatory cells isolated from PBMCs were exposed to Cladribine. mRNAbulk analysis was performed to evaluate metabolic and functional changes upon the treatment. 

Abstract

Immune reconstitution therapies for Multiple Sclerosis (MS) are based on selective lymphocyte reduction followed by repopulation and rescue of immune tolerance. Among these therapies, Cladribine is an adenosine analogue that interferes with cell division and depletes several lymphocyte subtypes. Regulatory T cells (Tregs), physiologically devoted to immune suppression, are dysfunctional in the context of MS.
Here, we explored the effects of Cladribine in vivo on Tregs in MS patients, and in vitro in cultured Tregs. We observed that, in vivo, Tregs were overall less sensitive than conventional T cells (Tconvs) to the depleting effect of Cladribine. This phenomenon was particularly evident  in  the subset of the resting (rest) Tregs. At baseline, while activated (act) Tregs presented markers of proliferation, senescence, and survival, restTregs highly expressed the antiapoptotic protein Bcl2 and the quiescence marker Bach2. In vitro, Cladribine strongly reduced Treg viability while inducing a program of senescence and dysfunction and compromising their metabolic fitness. When Treg dynamics were analyzed  ex vivo in relation to neuroinflammation and response to therapy, restTregs exhibited resistance to depletion in non-responders, in association with  increasing expression of Bcl2. 
These results indicate that efficacy of Cladribine therapy requires reduction and repopulation of the Treg compartment, an event that may be hindered by restTreg resistance, which is supported by antiapoptotic signals. 

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