Cutting Edge: Activation of Toll-Like Receptor 2 Induces a Th2 Immune Response and Promotes Experimental Asthma

Abstract

Recognition of microbial components by APCs and their activation through Toll-like receptors (TLR) leads to the induction of adaptive immune responses. In this study, we show that activation of TLR2 by its synthetic ligand Pam3Cys, in contrast to activation of TLR9 by immunostimulatory DNA (ISS-ODN), induces a prominent Th2-biased immune response. Activation of APCs by Pam3Cys resulted in the induction of Th2-associated effector molecules like IL-13, and IL-1β, GM-CSF and up-regulation of B7RP-1, but low levels of Th1-associated cytokines (IL-12, IFNα, IL-18, IL-27). Accordingly, TLR2 ligands aggravated experimental asthma. These data indicate that the type of TLR stimulation during the initial phase of immune activation determines the polarization of the adaptive immune response and may play a role in the initiation of Th2-mediated immune disorders, such as asthma.

Suppression of Early IL-4 Production Underlies the Failure of CD4 T Cells Activated by TLR-Stimulated Dendritic Cells to Differentiate into Th2 Cells

“…inhibit early IL-4 production by responding CD4 T cells and thus inhibit Th2 cell development. Our data indicating that TLR 2 ligands profoundly inhibit Th2 cell development are contradictory to those findings that have suggested the role of TLR2 ligands in the induction of Th2 responses (20,(33)(34)(35)(36)(37)(38). Nevertheless, there is a large body of published data that is consistent with our findings showing that TLR2 ligands, including Pam 3 Cys, either promote Th1 responses or inhibit Th2 responses (39 -47).…”

Toll-Like Receptor 2 Agonists Exacerbate Accelerated Nephrotoxic Nephritis

“…It is interesting that the low doses of LPS encouraged a predominant Th2-type response and tissue infiltration with eosinophils, whereas those that were given the higher dose produced a Th1 response and lung infiltration with neutrophils (12). When lipopeptide is used as an adjuvant with ovalbumin, it can exacerbate experimental asthma and produce an associated systemic Th2 response, which, unlike LPS, is not dose dependent (13). Another study investigated the effect of TLR2 agonists on established airway inflammation and discovered that lipopeptide actually attenuated disease, and this was associated with an increase in IFN-␥ and therefore predominant Th1-type response (11).…”

“…Five days later, mice received an injection of 160 l of NTS via the tail vein to induce disease. The dose of lipopeptide and NTS given were based on those used in other in vivo studies and on our own pilot studies (13). At 14 d after disease induction, mice were killed and exsanguinated for serum, and the kidneys were harvested.…”

“…It also has been demonstrated that activation of dendritic cells by specific TLR ligands can influence the development of an adaptive immune response both in vivo (7) and in vitro (11)(12)(13). TLR2 can be found on professional immune cells, including neutrophils, macrophages, and dendritic cells, but also on stromal cells throughout the body (14).…”

Toll-like receptor-mediated adjuvanticity and immunomodulation in dendritic cells: Implications for peptide vaccines

“…Our data showed that, neurotoxin, some fungal lysates and LPS from the mucosal pathogen Porphyromonas gingivalis bias immune responses towards Th2. [31][32][33][34][35] As there is evidence that TLR synergy can enhance immune responses, [36][37][38][39] the inclusion in a vaccine of multiple TLR agonists may prove highly beneficial. However, the extent to which TLR stimulation, especially that induced by combined TLR agonists, influences immunological potency and the overall Th1/Th2 balance of the immune response is largely unknown.…”