Interferon-λ Improves the Efficacy of Intranasally or Rectally Administered Influenza Subunit Vaccines by a Thymic Stromal Lymphopoietin-Dependent Mechanism

Abstract

Previous work showed that interferon-λ (IFN-λ) can trigger the synthesis of thymic stromal lymphopoietin (TSLP) by specialized epithelial cells in the upper airways of mice, thereby improving the performance of intranasally administered influenza vaccines. Here we demonstrate that protein-only influenza vaccines containing either IFN-λ or TSLP boosted antigen-specific IgG1 and IgA responses and enhanced the resistance of mice to influenza virus challenge, irrespective of whether the vaccines were applied via the intranasal or the rectal route. TSLP receptor deficiency negatively influenced vaccine-induced antiviral immunity by impairing the migration of dendritic cells from the airways to the draining lymph nodes of immunized mice, thereby restraining follicular helper T cell and germinal center B cell responses. As previously observed during intranasal vaccination, the adjuvant effect of IFN-λ on a rectally administered influenza vaccine was no longer observed when TSLP receptor-deficient mice were used for immunization, highlighting the central role of the IFN-λ/TSLP axis for vaccine-induced antiviral immunity in the mucosa.

IFN-λ is protective against lethal oralToxoplasma gondiiinfection

“…Treatment of mice with IFN-λ augmented weight recovery and reduced T. gondii brain colonization without affecting T. gondii cysts sizes (Figure 4A-D), confirming our results that IFN-λ acts early during T. gondii infection by limiting parasite dissemination. IFN-λ serves as an mucosal adjuvant, promoting humoral responses in a thymic stromal lymphopoietin (TSLP)-dependent manner 2,29 . Interestingly, we found higher levels of secreted IgG1 after 30 days of T. gondii infection in the IFN-λ-treated group compared to non-treated mice ( Suppl.…”

“…IFN-λ is therefore believed to act locally as the first line of defense against invading pathogens on mucosal surfaces possibly without activating the detrimental immune responses mediated by IFN type I 28,1,13 . IFN-λ has also been described to enhance adaptive immune responses at these sites 2,29 .…”

Increased expression of long-isoform thymic stromal lymphopoietin is associated with rheumatoid arthritis and fosters inflammatory responses

“…TSLP can drive allergic Th2 responses with the production of cytokines IL-4, IL-5, IL-13, and TNF-a via regulating OX40 ligand expression on DCs. Our work recently highlights the adjuvant activity of TSLP in inducing antiviral protective immunity (15,16). Moreover, TSLP has been implicated in chronic inflammation, autoimmune diseases, and cancer (11,(17)(18)(19)(20)(21).…”

Type III interferon exerts thymic stromal lymphopoietin in mediating adaptive antiviral immune response

“…The same results can be observed when TSLP is given together with another IAV vaccine haemagglutinin (HA), a commercial influenza vaccine containing particle-derived hemagglutinin. In TSLPR deficient ( Tslpr -/- ) mice, intranasal immunization with the IAV vaccine fails to boost neither antigen-specific IgG1 nor nucleoprotein-specific CD8 + T cells compared with WT mice ( 33 , 35 ). Taken together, these data verify the non-redundant role of TSLP in mucosal adaptive immunity, whether administrated alone or combined with vaccination.…”

“…With the further deepening of research, numerous reports regarding the responsibility of IFN-III in stimulating adaptive antiviral immunity continue to emerge ( 2 , 16 , 30 – 32 ). Particularly, the revealed mechanism of thymic stromal lymphopoietin (TSLP) unveils the mysterious role of IFN-III in orchestrating adaptive immune response ( 33 – 35 ). The assistance of TSLP in IFN-III-mediated immunoregulatory faculties triggers our interest in further research.…”