Th1 polarization of CD4+ T cells by toll-like receptor 3-activated human microglia

Toll-like receptors (TLRs) are expressed by human microglia and translate environmental cues into distinct activation programs. We addressed the impact of TLR ligation on the capacity of human microglia to activate and polarize CD4(+) T cell responses. As microglia exist under distinct states of activation, we examined both ramified and ameboid microglia isolated from adult and fetal CNS, respectively. In vitro, ligation of TLR3 significantly increased major histocompatibility complex and costimulatory molecule expression on adult microglia and induced high levels of interferon-alpha, interleukin-12p40, and interleukin-23. TLR4 and, in particular, TLR2 had a more limited capacity to induce such responses. Coculturing allogeneic CD4(+) T cells with microglia preactivated with TLR3 did not increase T cell proliferation above basal levels but consistently led to elevated levels of interferon-gamma secretion and Th-1 polarization. Fetal microglial TLR3 responses were comparable; in contrast, TLR2 and TLR4 decreased major histocompatibility complex class 11 expression on fetal cells and reduced CD4(+) T cell proliferation to levels below those found in untreated cocultures. All 3 TLRs induced comparable interleukin-6 secretion by microglia. Our findings illustrate how activation of human microglia via TLRs, particularly TLR3, can change the profile of local CNS immune responses by translating Th-1 polarizing signals to CD4(+) T cells.