Nanoparticles coated with fragments of the body's own proteins are shown to induce T cells of the immune system to adopt regulatory functions that suppress autoimmune reactions involving these self-antigens. See Article p.434
Autoimmune diseases arise when our immune system attacks our own tissues. The immune cells of affected individuals are insufficiently tolerant towards certain 'self' proteins and attack them as if they were foreign. Helper T cells (TH cells) play a central part in autoimmune diseases because they orchestrate the function of other cells in the immune system, including B cells, cytotoxic T cells and macrophages. Current treatments for autoimmune diseases tend to suppress the whole immune system or, at best, inhibit the movement or function of T cells; such approaches inevitably increase the risk of infection and cancer. The ideal treatment for autoimmune diseases would convert the function of TH cells from disease-causing to disease-regulating without affecting the rest of the immune system. In this issue, Clemente-Casares et al.1 (page 434) describe coated nanoparticles that mediate this conversion by binding to receptors on potentially self-reactive T cells.
The authors' approach can be considered as a type of antigen-specific immunotherapy. Antigens are the molecular structures that induce the activation of T or B cells; for T cells these are generally small fragments of proteins (peptides). Each T cell can express a different surface receptor, thereby allowing our immune system to respond to countless different antigens, including self-antigens. Antigen-specific immunotherapy is designed to dampen the immune response to a particular antigen or set of closely associated antigens. This concept has been used to treat allergies for more than a century2, but specific immunotherapy for autoimmune diseases lagged behind until the discovery that TH cells are activated by peptides bound to MHC class II proteins. This led to the design of peptides that selectively target TH cells without risking the activation of self-reactive cytotoxic T cells or B cells3.
How can exposure to a peptide known to stimulate self-reactive TH cells switch off the disease they cause? This is best explained by the 'two-signal' rule of T-cell activation4,5. All antigens, whether self or foreign, must be broken down into peptides, which must then bind MHC class II proteins and be displayed at the surface of antigen-presenting cells (APCs) to activate TH cells. This is referred to as signal 1. The APC must also upregulate co-stimulatory molecules, such as CD80 and CD86, to provide the second signal required for TH-cell survival and proliferation.
“The treatment drives the TH cell to differentiate into cells with characteristics of regulatory T cells; these act to dampen immune responses.”
What happens when TH cells receive signal 1, but not signal 2? Historically, this was thought to induce a state of unresponsiveness known as anergy6. Now, Clemente-Casares et al. show that treating TH cells with nanoparticles coated with a peptide bound to MHC class II proteins (pMHC-NP treatment) triggers signal 1 alone. But rather than simply inducing anergy, the treatment drives the TH cells to differentiate into cells that have characteristics of regulatory T cells; these act to dampen immune responses.
The resulting regulatory cells exert their function by secreting the anti-inflammatory proteins IL-10 and TGF-β. Furthermore, the cells express the transcription factor T-bet and make the cytokine signalling molecule IFN-γ during their differentiation. These characteristics imply that they derive from cells of the TH1 subset of TH cells (Fig. 1). The differentiation of IL-10-secreting T cells — referred to here as TR1-like cells — from TH1 cells is an immunoregulatory mechanism known to prevent excessive immune responses to a range of infections7,8,9. These cells mediate a negative feedback mechanism involving suppression of co-stimulatory molecules on APCs and a reduction in the inflammatory proteins secreted by APCs10.
What are the downstream effects of the TR1-like cells induced by pMHC-NP treatment? Clemente-Casares et al. show that the cells suppress the function of APCs and reinforce immune regulation by promoting IL-10 production by B cells (Fig. 1). The authors verify the specificity of their approach by using different experimental models of autoimmune disease. pMHC-NPs carrying peptides from collagen, an antigen derived from joints, suppressed disease in a mouse model of rheumatoid arthritis, but not in mice with experimental autoimmune encephalitis (EAE), a model of multiple sclerosis. Conversely, pMHC-NPs carrying peptides of antigens from the central nervous system controlled EAE but not collagen-induced arthritis. This confirms that the immune regulation induced by pMHC-NP treatment is specific to the antigen and tissue, and so to the disease.
Furthermore, the pMHC-NPs did not need to target T cells specific for all peptides in the affected organ. Even peptides from sub-dominant antigens (weaker antigens that do not trigger disease in the first place) were able to induce TR1-like cells that suppressed helper and cytotoxic T cells with activity against other antigens (Fig. 1). Thus, although this treatment is highly antigen-specific at the induction phase, it can influence other arms of the immune response locally, through induction of regulatory B-cell activity and suppression of helper and cytotoxic T cells specific for different antigens. This requires that the peptide fragment from the inducing antigen and the other antigens are presented by the same APC.
Is it possible that such bystander suppression could lead to systemic immune suppression by switching off cells not involved in the autoimmune response, thereby increasing the risk of infection or cancer? No: bystander suppression will be limited to lymph nodes associated with the affected organ and will influence only those APCs presenting the relevant self-antigen. Such specificity is clearly demonstrated by Clemente-Casares and colleagues — mice treated with pMHC-NPs are protected against the relevant autoimmune disease, yet show undiminished responses to infections and foreign antigens.
The experimental treatments in this study use well-characterized models of autoimmune disease. But is this work just another therapeutic approach that works in mice but will never work in humans? It seems not: the authors show that pMHC-NP treatment leads to differentiation and proliferation of human TR1-like cells in immunodeficient mice transplanted with human T and B cells, demonstrating that pMHC-NP treatment works on human cells. The team's work also suggests that treatment with pMHC-NPs is more effective than with monomers of MHC-bound peptides at an equivalent dose. Furthermore, pMHC-NP treatment seems to be more suppressive than the application of peptide alone; however, the doses and routes of administration in these tests were not comparable.
There is overwhelming evidence that peptide antigens can induce TR1-like cells11 and suppress autoimmune diseases in both mice and humans9. The fact that pMHC-NP treatment induces TR1-like cells similar to those seen after the administration of peptide alone suggests that pMHC-NPs mimic the APC to which therapeutic peptides bind in vivo. The challenge with each of these approaches will be to find the optimal dose and route of administration for treating people. As these options progress towards clinical trials, it is vital that their mechanism of action is investigated in detail so that patients can benefit fully from antigen-specific immunotherapy for autoimmune disease.Footnote 1
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The author declares competing financial interests. See go.nature.com/ukjrkv for details.
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