TLR2 and TLR4 differentially regulate B7-1 resulting in distinct cytokine responses to the mycoplasma superantigen MAM as well as to disease induced by Mycoplasma arthritidis

Abstract

SummaryMycoplasma arthritidis mitogen (MAM) is a superantigen secreted by M. arthritidis , an agent of murine arthritis and toxicity. We previously demonstrated that C3H mouse sub-strains differing in expression of Tolllike receptor 4 (TLR4), differed in immune reactivity to MAM due to differential engagement of TLR2 and TLR4. Here we examine the role of B7 co-stimulatory molecules in immune outcome and disease manifestations resulting from these different MAM/TLR2 and MAM/TLR4 interactions. Injections of MAM into C3H/ HeJ mice upregulated expression of B7-1 but not B7-2 on peritoneal adherent cells, whereas B7-1 expression was lower on cells from C3H/HeSnJ mice. Anti-B7-1 antibody but not anti-B7-2, injected in vivo , changed the type 1 cytokines in MAM-injected C3H/ HeJ mice to a type 2 cytokines and, conversely, the type 2 response in C3H/HeSnJ mice injected with anti-B7-1 shifted to a type 1 pattern. Whereas anti-B7-2 exerted no effect on disease in either mouse strain, anti-B7-1 significantly delayed the lethal toxicity of M. arthritidis in C3H/HeJ mice but enhanced arthritis in C3H/HeSnJ mice. Thus, TLR-mediated regulation of B7-1 results in diverse cytokine profiles in C3H substrains, and that the interaction of MAM with different TLR(s) may differentially affect cytokine responses and ultimately, M. arthritidis disease.

The bacterial superantigen and superantigen‐like proteins

“…MAM causes elevated pro‐inflammatory cytokine response in inbred C3H/HeJ mice, which carry a defect in the Toll‐like receptor 4 (TLR‐4) and are highly susceptible to toxic shock (57). Variations in cytokine MAM responses between different mouse strains results from differential engagement of TLR‐2 and TLR‐4 (58) and subsequently differential regulation of B7‐1 (57). Recently, MAM has been shown to have DNase activity (59).…”

Mycoplasma superantigen initiates a TLR4-dependent Th17 cascade that enhances arthritis after blocking B7-1 inMycoplasma arthritidis-infected mice

“…C3H/HeJ) develop a Th1‐type immune response (Mu et al ., ). We also reported that manipulation of B7‐1 (CD80) but not B7‐2 (CD86) function can modulate Th1/Th2 immune responses depending upon presence or absence of TLR4 in mice injected with MAM SAg or in mice infected with live mycoplasma (Mu et al ., ). Previously, we demonstrated that blocking of B7‐1 could enhance arthritis in mice infected with M. arthritidis (Mu et al ., ).…”

Bacterial superantigens and superantigen-like toxins

“…Neutralization of B7-1 changed the Th1-type response to a Th2-type response in MAM-injected TLR4-defective mice and delayed the lethal toxicity of MAM. Conversely, wild-type mice showed a shift from Th2 to Th1 and enhanced arthritis when B7-1 was blocked, suggesting a role of B7-1 in cytokine responses to MAM stimulation [216]. It was also demonstrated that interactions of MAM with TLR2 and TLR4 differentially regulate IL-17 and Th17-associated cytokines [217].…”