The capacity to achieve sufficient concentrations of Ag-specific Ab of the appropriate isotypes is a critical component of immunity that requires efficient differentiation and interactions of Ag-specific B and T helper (Th) cells along with dendritic cells. Numerous bacterial toxins catalyze mono-(ADP-ribosyl)ation of mammalian proteins to impact cell physiology and adaptive immunity. However, little is known about biological functions of intracellular mammalian mono-(ADP-ribosyl)transferases (mART), such as any ability to regulate Ab responses. Poly-(ADP-Ribose) Polymerase 14 (PARP14), an intracellular protein highly expressed in lymphoid cells, binds to STAT6 and encodes a catalytic domain with mART activity. Here we show that recall IgA as well as the STAT6-dependent IgE Ab responses are impaired in PARP14-deficient mice. Whereas PARP14 regulation of IgE involved a B cell intrinsic process, the predominant impact on IgA was B cell-extrinsic. Of note, PARP14 deficiency reduced the levels of Th17 cells and CD103+ DCs which are implicated in IgA regulation. PARP14 enhanced the expression of RORα, Runx1 and Smad3 after T cell activation, and, importantly, its catalytic activity of PARP14 promoted Th17 differentiation. Collectively, the findings show that PARP14 influences the class distribution, affinity repertoire, and recall capacity of antibody responses in mice, and provide direct evidence of requirement for protein mono-ADP-ribosylation in T helper differentiation.
Control of the protozoan parasite, Leishmania major, is dependent upon establishing a robust T cell response. An early event in the development of an effective T cell response is the expansion (or hypertrophy) of the lymph node draining the site of infection, although the mechanisms involved in this response are not completely understood. Here we show that lymph node hypertrophy following L. major infection in mice is associated with increased recruitment of lymphocytes to the lymph node from the blood, and that CD62L-deficient mice, which are unable to recruit cells to the lymph node, develop a chronic infection with L. major. Injection of L. major activated dendritic cells promoted lymph node hypertrophy, and this correlated with an increase in the expression of CCR7 on dendritic cells, although the upregulation of CCR7 occurred on the bystander (uninfected) dendritic cells rather than those containing parasites. We found that increased CCR7 expression was TLR9 dependent, that TLR9−/− DCs migrated less efficiently to the draining lymph node, and that TLR9−/− mice exhibited a deficit in lymph node expansion following L. major infection, as well as increased susceptibility. Taken together, these results are the first to demonstrate that activation of dendritic cells via TLR9 is essential for the induction of lymph node hypertrophy in leishmaniasis.
IL-18 has been shown to play a critical role in cytokine-induced organ failure during endotoxic shock. Human monocytotropic ehrlichiosis (HME) is a tick-borne infectious disease caused by E. chaffeenesis. HME is modeled in B6 mice using Ehrlichia muris (EM) that cause mild disease, and Ixodes ovatus Ehrlichia (IOE) that cause fatal shock-like syndrome. As Ehrlichia-induced septic shock and tissue injury is associated with increased IL-18 production, we examined the effect of blocking IL-18 signaling via IL-18Rβ on host defense & immune responses following sublethal (EM) and lethal (IOE) infection. Compared to IOE-infected isotype controls, in vivo IL-18Rβ neutralization in IOE-infected mice decreased bacterial burden, increased frequency of IFN-γ producing NK and NKT cells and enhanced production of TNF-α by T and non T cells on day 2 post-infection. On day 7 post-infection, blocking IL-18Rβ in lethally infected mice did not significantly influence the acquired pathogenic immune responses compared to lethally-infected isotype controls. Interestingly, blocking IL-18Rβ in the EM-infected mice increased bacterial burden, which was associated with suppressed early production of TNF-α and IFN-γ by different cell subsets compared to EM-infected isotype controls. These data suggest that IL-18Rβ may play dual protective and pathogenic roles in sublethal and lethal ehrlichial infection, respectively, through regulation of IFN-γ and TNF-α production by different innate cell subsets.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.