A new Treg subset on the block, and a clue to understand IFNβ efficacy in the treatment of multiple sclerosis

IFNβ has been used in the treatment of multiple sclerosis (MS) for about two decades, however the molecular mechanisms underlying its efficacy in preventing and/or limiting relapses or disease progression are poorly understood. Perhaps even more importantly, it also remains unknown why a subset of patients with MS does not respond to IFNβ therapy.

In a study recently published in Nature Medicine, researchers from the University of Copenhagen offer a new clue to understand how IFNβ exerts its therapeutic effect in MS by describing a new type of regulatory T  (Treg) cells.

Called FoxA1⁺ Treg cells, these cells are present in the central nervous system (CNS) of mice in a model of MS and display suppressive and killing properties towards activated T cells. Interestingly, they can be induced in vitro by IFNβ and are found in greater proportions in the blood of MS patients responding to IFNβ treatment compared to patients who do not respond to IFNβ therapy.

Different mechanisms have been suggested to explain the observed therapeutic effect of IFNβ in MS, for example modification of the blood-brain barrier or antagonizing of deleterious Th17 responses. In this study, Liu et al. were interested in the possibility that IFNβ has a beneficial effect in MS by modulating regulatory T cell responses (which in turn limit activated autoreactive T cell-derived inflammation and tissue damage in the CNS).

Using a mouse model of relapsing-remitting MS (in which IFNβ-deficient mice develop a more severe disease than wild-type mice), the authors found no difference in the numbers of conventional CD4⁺CD25⁺Foxp3⁺ Treg cells present in the CNS of wild-type mice and in the CNS of IFNβ-deficient mice. However, they detected in the CNS of wild-type mice a population of CD4⁺ T cells that was absent in the CNS of IFNβ-deficient mice; that population was characterized by a high expression of the cell surface molecule PD-L1 (programmed cell death ligand 1).

Starting with ex vivo cultures of CD4⁺ T cells that are specific for myelin basic protein (MBP) and that can induce an MS-like disease in mice upon transfer, Liu et al. showed that development of CD4⁺PD-L1^hi T cells could be induced in vitro by co-culturing the MBP-specific T cells with neurons. Analysis of gene expression profile for these cells revealed that they expressed the transcription factor FoxA1 and that they had a distinct profile from conventional Foxp3⁺ Treg cells. Nevertheless, these CD4⁺PD-L1⁺FoxA1⁺ T cells turned out to have regulatory properties in vitro, suppressing T cell proliferation and inducing cell death in activated T cells. Additional experiments showed that the suppressive properties of FoxA1⁺ Treg cells were dependent on both FoxA1 and PD-L1 (FoxA1 inducing the expression of PD-L1, and PD-L1 mediating the antiproliferative and killing effect via binding to PD-1 on the surface of activated T cells).

Linking back to the therapeutic role of IFNβ in MS, the authors showed that FoxA1⁺ Treg cells could be induced in vitro by IFNβ treatment of both mouse and human CD4⁺ T cells. Looking at patients with relapsing-remitting MS who either responded well to IFNβ therapy (2-year treatment) or did not, Liu et al. found that the proportion of FoxA1⁺ Treg cells in blood at baseline was comparable in both groups but increased after IFNβ treatment only in patients who clinically responded to IFNβ therapy.

Altogether, the data presented in this study suggest that IFNβ beneficial effect in the treatment of MS may be mediated in part by the induction of a new type of regulatory T cells that express the transcription factor FoxA1 and the cell surface molecule PD-L1. Of course, the findings need to be confirmed in other studies, and it is likely that the picture of FoxA1⁺ Treg cells painted in this initial study will be altered over time, as the cells get further characterized and more precisely defined.

For now, a few questions can already be raised. Are FoxA1⁺ Treg cells only to be found in the CNS niche in the context of MS, or will they also be detected in other tissues in the context of other inflammatory autoimmune diseases? What are the factors inducing their differentiation besides IFNβ? Is PD-L1 their main effector molecule? It is also intriguing to note that, although the authors used the expression of CD4 and PD-L1 (high) to identify FoxA1⁺ Treg cells in MS patients, not all of the CD4⁺PD-L1^hi T cells expressed FoxA1, and the proportion of CD4⁺PD-L1^hi T cells expressing FoxA1 varied among MS patients (at baseline and even more so after IFNβ treatment in responders). This definitely warrants further investigation to better define FoxA1⁺ Treg cells. Additionally, it will be interesting to try and understand why the levels of FoxA1⁺ Treg cells increase in some MS patients upon IFNβ treatment but not in others, why there is so much heterogeneity, and how much it contributes to how well a patient responds to IFNβ therapy.

Reference
FoxA1 directs the lineage and immunosuppressive properties of a novel regulatory T cell population in EAE and MS. Liu Y, Carlsson R, Comabella M, Wang J, Kosicki M, Carrion B, Hasan M, Wu X, Montalban X, Dziegiel MH, Sellebjerg F, Sørensen PS, Helin K, Issazadeh-Navikas S. Nat Med. 2014 Mar;20(3):272-82. doi: 10.1038/nm.3485
PMID: 24531377

Liu Y, Carlsson R, Comabella M, Wang J, Kosicki M, Carrion B, Hasan M, Wu X, Montalban X, Dziegiel MH, Sellebjerg F, Sørensen PS, Helin K, & Issazadeh-Navikas S (2014). FoxA1 directs the lineage and immunosuppressive properties of a novel regulatory T cell population in EAE and MS. Nature medicine, 20 (3), 272-82 PMID: 24531377