T follicular helper (Tfh) cells constitute a specialized subset of effector CD4+ T cells, which help B cells undergo class switching, as well as antibody affinity maturation in germinal centers during humoral immune responses [1]. Tfh cells are defined by high expression of surface markers CXCR5, ICOS and PD1, which facilitate the migration of Tfh cells toward B cell follicles and ensure their interaction with B cells [[2], [3], [4]]. The transcription factor (TF) BCL6 is the lineage-defining factor for Tfh cells and is critical for Tfh differentiation and maintenance [5,6]. As a transcriptional repressor, BCL6 can directly bind and suppress non-Tfh-associated genes like Tbx21, Gata 3, and Rora. It can also indirectly upregulate expression of Tfh-associated genes such as Cxcr5 and Pdcd1 via repression of transcription repressors like BLIMP1 [6,7].

Dysregulated Tfh cells can disturb GC reactions and generate autoreactive antibodies with the potential to induce autoimmune diseases. For example, increased circulating Tfh (cTfh) cells in peripheral blood have often been found in patients with SLE, a typical autoimmune disease mediated by autoantibodies [8,9]. Tfh cell numbers also increase in lupus animal models, in parallel to disease development and progression. Furthermore, genetic deficiency of genes such as P2rx7 [10], Def 6, Swap 70 [11] and Srsf1 [12] can increase Tfh cell numbers and lead to spontaneous or aggravated lupus in mice. In contrast, inhibiting the development of Tfh in mice can prevent the progression of SLE [13,14]. Therefore, targeting Tfh cells may be a feasible approach to control autoimmune diseases like SLE.

Phosphatase PP2A is one of the major Ser/Thr phosphatases in eukaryotes, which is critical for many cellular functions including cell survival, proliferation, activation, and differentiation. PP2A is composed of three subunits, a structural A, a regulatory B, and a catalytic C subunit. The PP2A C subunit has two isoforms (PP2A Cα and PP2A Cβ), and the expression of PP2A Cα is ten times higher than PP2A Cβ [15,16]. It has been reported that PP2A Cα protein expression levels are elevated in peripheral T cells of SLE patients and positively correlate with disease activities [8]. PP2A has been reported to be essential in Th17 cell differentiation and requisite for the regulatory function of Treg cells [17,18]. However, evidence from these studies is not sufficient to establish a solid link between PP2A and SLE. For example, despite the overwhelming evidence that IL17 contributes to lupus pathology, IL17A deficiency in lupus prone MRL/lpr mice or IL17A neutralization in NZB/NZW mice does not affect the course of nephritis [19]. Furthermore, the function of PP2A in Treg cells would be predicted to promote immune tolerance rather than autoimmunity [18]. Lastly, it has been suggested that PP2A expression promotes SLE by diminishing IL2 production, but low dose recombinant human IL2 treatment in lupus could not restore the aberrant Tfh expansion to normal levels [20]. In addition, other autoimmune diseases like rheumatoid arthritis (RA), in which there is lower IL2 levels but equal expression of PP2A compared to healthy controls, have conflicting data regarding Tfh cell frequencies [8,21]. Given the critical role of Tfh cells in SLE, the fundamental question of whether PP2A affects the differentiation and function of Tfh cells and contributes to the production of autoreactive antibodies in SLE remains an important question.

In our present study, we demonstrate that PP2A is essential for Tfh differentiation. We further show that PP2A deficiency translationally downregulated BCL6 expression via the mTORC1-4EBP-eIF4E axis. Additionally, both PP2A T cell deficiency and PP2A inhibition significantly protected mice from lupus with fewer auto-antibodies in serum and milder injuries in kidney. Finally, we confirmed a positive correlation between PP2A Cα and BCL6 protein expression in CD4+ T cells of lupus patients. Overall, our study suggests that PP2A is a potential therapeutic target for the treatment of SLE.