IL-10 inhibition during immunization improves vaccine-induced protection against Staphylococcus aureus infection.

Staphylococcus aureus is a major human pathogen. An effective anti-S. aureus vaccine remains elusive as the correlates of protection are ill-defined. Targeting specific T cell populations is an important strategy for improving anti-S. aureus vaccine efficacy. Potential bottlenecks that remain are S. aureus-induced immunosuppression and the impact this might have on vaccine-induced immunity. S. aureus induces IL-10, which impedes effector T cell responses, facilitating persistence during both colonization and infection. Thus, it was hypothesized that transient targeting of IL-10 might represent an innovative way to improve vaccine efficacy. In this study, IL-10 expression was elevated in the nares of persistent carriers of S. aureus, and this was associated with reduced systemic S. aureus-specific Th1 responses. This suggests that systemic responses are remodeled because of commensal exposure to S. aureus, which negatively implicates vaccine function. To provide proof of concept that targeting immunosuppressive responses during immunization may be a useful approach to improve vaccine efficacy, we immunized mice with T cell-activating vaccines in combination with IL-10-neutralizing antibodies. Blocking IL-10 during vaccination enhanced effector T cell responses and improved bacterial clearance during subsequent systemic and subcutaneous infection. Taken together, these results reveal a potentially novel strategy for improving anti-S. aureus vaccine efficacy.

Nasal vaccines for pertussis.

Whooping cough, caused by Bordetella pertussis, is still a major cause of morbidity and mortality worldwide. Current acellular pertussis (aP) vaccines induce potent circulating IgG and prevent severe disease in children/adults and in infants born to vaccinated mothers. However, they do not prevent nasal infection, allowing asymptomatic transmission of B. pertussis. Studies in animal models have demonstrated that, unlike natural infection, immunization with aP vaccines fails to induce secretory immunoglobulin A (IgA) or interleukin-17 (IL-17)-secreting tissue-resident memory CD4 T (TRM) cells, required for sustained sterilizing immunity in the nasal mucosa. Live-attenuated vaccines or aP vaccines formulated with novel adjuvants that induce respiratory IgA and TRM cells, especially when delivered by the nasal route, are in development and have considerable promise as next-generation vaccines against pertussis.

Retinoic acid-induced autoantigen-specific type 1 regulatory T cells suppress autoimmunity.

Regulatory T (Treg) cells help to maintain tolerance and prevent the development of autoimmune diseases. Retinoic acid (RA) can promote peripheral conversion of naïve T cells into Foxp3+ Treg cells. Here, we show that RA can act as an adjuvant to induce antigen-specific type 1 Treg (Tr1) cells, which is augmented by co-administration of IL-2. Immunization of mice with the model antigen KLH in the presence of RA and IL-2 induces T cells that secrete IL-10, but not IL-17 or IFN-γ, and express LAG-3, CD49b and PD-1 but not Foxp3, a phenotype typical of Tr1 cells. Furthermore, immunization of mice with the autoantigen MOG in the presence of RA and IL-2 induces Tr1 cells, which suppress pathogenic Th1 and Th17 cells that mediate the development of experimental autoimmune encephalomyelitis (EAE), an autoimmune disease of the CNS. Furthermore, immunization with a surrogate autoantigen, RA and IL-2 prevents development of spontaneous autoimmune uveitis. Our findings demonstrate that the induction of autoantigen-specific Tr1 cells can prevent the development of autoimmunity.

Retinoic acid suppresses IL-17 production and pathogenic activity of γδ T cells in CNS autoimmunity.

Retinoic acid (RA) in the steady state enhances induction of Foxp3(+) regulatory T (Treg) cells and inhibits differentiation of Th1 and Th17 cells, thereby maintaining tolerance, but can in inflammatory conditions promote effector Th1 and Th17 cells that mediate inflammation. IL-17-producing γδ T cells have recently been shown to have a major pathogenic role in autoimmune diseases. Here, we examined the immunomodulatory effects of RA on γδ T cells. We found that RA had a dramatic suppressive effect on IL-17A and IL-17F production by γδ T cells stimulated with IL-1ß and IL-23. RA suppressed RORγt, IL-1R and IL-23R expression in γδ T cells. Treatment of mice with RA suppressed IL-17 production by γδ T cells in vivo. Furthermore, treatment of T cells with RA attenuated their ability to induce disease in experimental autoimmune encephalomyelitis (EAE), a murine model for multiple sclerosis. This was associated with a reduction in the number of central nervous system-infiltrating γδ T cells, but also CD4(+) T cells that produced IL-17A, IL-17F or GM-CSF. Interestingly, treatment of γδ T cells with RA or removal of γδ T cells from a bulk population of T cells significantly reduced their capacity to induce EAE, demonstrating a critical role for γδ T cells in promoting pathogenic Th17 cells. Our findings demonstrate that the anti-inflammatory properties of RA are mediated in part by suppressing STAT3-mediated activation of cytokine production and cytokine receptor expression in γδ T cells, which suppresses their ability to activate Th17 cells.