Summary The contribution of Toll-like receptor (TLR) signaling to T cell-dependent (TD) antibody responses was assessed by using mice lacking the TLR signaling adaptor MyD88 in individual cell types. When a soluble TLR9 ligand was used as adjuvant for a protein antigen, MyD88 was required in dendritic cells but not in B cells to enhance the TD antibody response, regardless of the inherent immunogenicity of the antigen. In contrast, a TLR9 ligand contained within a virus-like particle substantially augmented the TD germinal center IgG antibody response, and this augmentation required B cell MyD88. The ability of B cells to discriminate between antigens based the physical form of a TLR ligand likely reflects an adaptation to facilitate strong anti-viral antibody responses.

Toll-like receptors (TLRs) play an important role in host defense against a variety of microbial pathogens. We addressed the mechanism by which TLRs contribute to host defense against the lethal parasite Toxoplasma gondii by using mice with targeted inactivation of the TLR adaptor protein myeloid differentiation primary response gene 88 (MyD88) in different innate cell types. Lack of MyD88 in dendritic cells (DCs), but not in macrophages or neutrophils, resulted in high susceptibility to the T. gondii infection. In the mice deficient in MyD88 in DCs, the early IL-12 response by DCs was ablated, the IFN-γ response by natural killer cells was delayed, and the recruited inflammatory monocytes were incapable of killing the T. gondii parasites. The T-cell response, although attenuated in these mice, was sufficient to eradicate the parasite during the chronic stage, provided that defects in DC activation were compensated by IL-12 treatment early after infection. These results demonstrate a central role of DCs in orchestrating the innate immune response to an intracellular pathogen and establish that defects in pathogen recognition by DCs can predetermine sensitivity to infection.innate immunity | host-pathogen interactions | natural killer cells

Cervical mucosal expression of cytokines involved in mediating cellular immunity is believed to influence the persistence of human papillomavirus (HPV) infection, a necessary prerequisite for the development of cervical intraepithelial neoplasia (CIN). Additionally, regulatory T (Treg) cells are increasingly understood to be important modulators of cellular immunity. Using quantitative RT-PCR, we measured, in cross-sectional design, the cervical mRNA expression of IFN-c, IL-10, and IL-12, as well as the Treg transcription factor Forkhead box P3 (Foxp3), in a cohort of young women representing CIN 1, 2, and 3, as well as benign histology. Higher levels of IFN-c and IL-10 were significantly (p ≤ 0.05) associated with decreased odds of having high-grade cervical disease (CIN 2 or 3) in multivariate logistic regression models. In contrast, higher levels of mucosal Foxp3 expression were associated with increased odds of having CIN 2 or 3 (p 5 0.004). In a multivariate model including cervical infection with HPV16 and/or another high-risk HPV type, Foxp3 remained higher in the CIN 2/3 group, but the difference was notably less significant (p 5 0.05). These findings support a model in which diminished cellular immunity in the cervical mucosa and mucosal enrichment of Treg cells both contribute to the development of high-grade lesions. ' 2008 Wiley-Liss, Inc.Key words: cervical intraepithelial neoplasia; papillomavirus infections; cytokines; regulatory T cells; mucosal immunology Human papillomavirus (HPV) persistence is necessary for the development of cervical intraepithelial neoplasia (CIN) 2 and 3 as well as cervical cancer. Among factors that influence the likelihood of a cervical HPV infection becoming persistent, the host's cellmediated immune response and the T helper type 1 (Th1) cytokine axis are likely to be key. Studies have shown diminished reactivity against HPV antigens in peripheral blood of women with highgrade CIN compared with women with HPV infections but without lesions. 1,2 Because immune parameters, such as cytokine levels, do not necessarily correlate between peripheral blood and the cervical mucosa, 3 the study of local responses is regarded as important in fully understanding the host response to HPV and cervical disease. 4 We have previously measured cytokine mRNA expression in exfoliated cervical cells and demonstrated that a Th1 cytokine profile is associated with subsequent HPV clearance. 5 In the past few years, a subset of cells that are able to modulate immune responses has come under intensive inquiry. These CD4 1 CD25 hi regulatory T (Treg) cells appear to act principally via a contact-dependent mechanism of suppression. 6 Intracellular expression of the Forkhead box P3 (Foxp3) transcription factor is considered to be the most reliable marker to date for Treg cells. 7,8 Various lines of evidence suggest that Treg cells are able to dampen anti-tumor immunity in a variety of human cancers, 9 and have been reported to be increased in both stroma and intraepithelial tissues in cervical ca...

No abstract

No abstract