Helios Expression Is Downregulated on CD8+ Treg in Two Mouse Models of Lupus During Disease Progression

Abstract

T-cell–mediated autoimmunity reflects an imbalance in this compartment that is not restored by tolerogenic immune cells, e.g., regulatory T cells or tolerogenic dendritic cells (tolDCs). Although studies into T-cell equilibrium have mainly focused on regulatory CD4+FoxP3+ T cells (CD4+ Tregs), recent findings on the lesser known CD8+ Tregs (CD44+CD122+Ly49+) have highlighted their non-redundant role in regulating lupus-like disease and their regulatory phenotype facilitated by the transcription factor Helios in mice and humans. However, there are still remaining questions about Helios regulation and dynamics in different autoimmune contexts. Here, we show the absence of CD8+ Tregs in two lupus-prone murine models: MRL/MPJ and MRL/lpr, in comparison with a non-prone mouse strain like C57BL/6. We observed that all MRL animals showed a dramatically reduced population of CD8+ Tregs and a greater Helios downregulation on diseased mice. Helios induction was detected preferentially on CD8+ T cells from OT-I mice co-cultured with tolDCs from C57BL/6 but not in MRL animals. Furthermore, the Helios profile was also altered in other relevant T-cell populations implicated in lupus, such as CD4+ Tregs, conventional CD4+, and double-negative T cells. Together, these findings could make Helios a versatile maker across the T-cell repertoire that is capable of differentiating lupus disease states.

Helios as a Potential Biomarker in Systemic Lupus Erythematosus and New Therapies Based on Immunosuppressive Cells

“…Nonetheless, few studies have assessed the relative expression of Helios in specific subpopulations of immune cells beyond simply distinguishing between Helios + and Helios − cells. In this sense, the merits of distinguishing up to three biologically relevant levels of Helios expression is currently being explored (Helios high , Helios mid , and Helios low ) [ 72 , 73 ].…”

“…From this model, with deficient TGF-β signaling, expression of this cytokine may influence the Helios expressed by CD8 + T cells [ 41 ]. In addition, we found that both the reduction in the proportion of Ly49 + CD8 + T cells and the weaker Helios expression by these cells was correlated to disease progression in two mouse models of lupus (MRL/MPJ and MRL/LPR) [ 73 ].…”

“…First, in mice, the global absence of Helios triggers an autoimmune phenomenon reminiscent of SLE [ 38 , 63 ]. Moreover, in classic murine SLE models like the MRL/LPR and MRL/MPJ mice, there are low levels of Helios in the Ly49 + CD8 + T cell populations [ 73 ]. Very recently, a lupus-like phenotype was diagnosed in a patient with a germline mutation in the IKZF2 gene [ 64 ].…”

“…As all analyses of Helios expression have been undertaken in patients with an evident pathology, its subclinical value is difficult to ascertain. Nevertheless, in asymptomatic MRL/MPJ and MRL/LPR animals (see Section 5.2 ), differential expression of Helios can be seen prior to disease manifestation and reflecting the future disease course: slow and mild (MRL/MPJ), or fast and severe (MRL/LPR) [ 73 ]. Finally, flow cytometry is a well-established experimental procedure in hospitals and immunology laboratories, and it is permanently undergoing advances [ 147 ].…”

“…This behavior could provide added value to this transversal T linage biomarker. For example, Helios was expressed more strongly in CD4 + Treg and Tconv populations in two murine models of lupus, yet more weakly by γδ T, DN T, and Ly49 + CD8 + Treg cells during the progression of the disease [ 73 ]. Perhaps the Helios hi profile of the CD4 + Treg fraction reflects a stronger activation and effector phenotype of these cells, a compensatory mechanism that is unable to combat the autoimmune imbalance.…”