Maintenance of IL-12-responsive CD4+ T cells during a Th2 response inLeishmania major-infected mice

Self Cite

Circulating autoantibodies against dsDNA and chromatin are a characteristic of systemic lupus erythematosus in humans and many mouse models of this disease. B cells expressing these autoantibodies are normally regulated in nonautoimmune-prone mice but are induced to secrete Abs following T cell help. Likewise, anti-chromatin autoantibody production is T cell-dependent in Fas/Fas ligand (FasL)-deficient (lpr/lpr or gld/gld) mice. In this study, we demonstrate that Th2 cells promote anti-chromatin B cell survival and autoantibody production in vivo. FasL influences the ability of Th2 cells to help B cells, as Th2-gld/gld cells support higher titers of anti-chromatin Abs than their FasL-sufficient counterparts and promote anti-chromatin B cell participation in germinal centers. Th1 cells induce anti-chromatin B cell germinal centers regardless of FasL status; however, their ability to stimulate anti-chromatin Ab production positively correlates with their level of IFN-γ production. This distinction is lost if FasL-deficient T cells are used: Th1-gld/gld cells promote significant titers of anti-chromatin Abs regardless of IFN-γ production levels. Thus, FasL from effector T cells plays an important role in determining the fate of anti-chromatin B cells.

“…Both the IFN-␥ high and IFN-␥ low intracellular cytokine levels are within the range of those reported by others for Th1-deviated cultures (41,42,49,50).…”

Section: Cells) a Low Frequency Of Cd4supporting

confidence: 88%

The Influence of Effector T Cells and Fas Ligand on Lupus-Associated B Cells

Fields

Nish

Hondowicz

et al. 2005

Self Cite

“…1G). Because continuous IL-12 is required for maintenance of anti-Leishmania immunity in healed mice (19)(20)(21), these observations suggest the existence of an alternative pathway for IL-12 production in CD40 KO mice that is nonfunctional or absent in CD40L KO mice. They further suggest that in the infected CD40L KO mice, exogenous IL-12 treatment is important for initiating a protective immune response but is unable to prevent disease progression once lesion has developed.…”

Section: Resultsmentioning

confidence: 91%

“…Treatment with rIL-12 leads to healing in CD40 KO mice, but not CD40L KO mice IL-12 produced by DCs is important for the development of naive CD4 + T cells into Th1 cells that mediate and maintain immunity in cutaneous leishmaniasis (19)(20)(21). Although some studies show that CD40-CD40L interaction is critical for IL-12 and the development of protective anti-Leishmania immunity (7), others show that CD40L-deficient mice are capable of producing IL-12 and mounting a protective Th1 response against L. major infection (8,9).…”

Section: Resultsmentioning

confidence: 99%

Interaction of Macrophage Antigen 1 and CD40 Ligand Leads to IL-12 Production and Resistance in CD40-Deficient Mice Infected with Leishmania major

Okwor

Jia

Uzonna

2015

Although some studies indicate that the interaction of CD40 and CD40L is critical for IL-12 production and resistance to cutaneous leishmaniasis, others suggest that this pathway may be dispensable. In this article, we compared the outcome of Leishmania major infection in both CD40- and CD40L-deficient mice after treatment with rIL-12. We show that although CD40 and CD40L knockout (KO) mice are highly susceptible to L. major, treatment with rIL-12 during the first 2 wk of infection causes resolution of cutaneous lesions and control of parasite replication. Interestingly, although treated CD40 KO mice remained healed, developed long-term immunity, and were resistant to secondary L. major challenge, treated CD40L KO reactivated their lesion after cessation of rIL-12 treatment. Disease reactivation in CD40L KO mice was associated with impaired IL-12 and IFN-γ production and a concomitant increase in IL-4 production by cells from lymph nodes draining the infection site. We show that IL-12 production by dendritic cells and macrophages via CD40L–macrophage Ag 1 (Mac-1) interaction is responsible for the sustained resistance in CD40 KO mice after cessation of rIL-12 treatment. Blockade of CD40L–Mac-1 interaction with anti–Mac-1 mAb led to spontaneous disease reactivation in healed CD40 KO mice, which was associated with impaired IFN-γ response and loss of infection-induced immunity after secondary L. major challenge. Collectively, our data reveal a novel role of CD40L–Mac-1 interaction in IL-12 production, development, and maintenance of optimal Th1 immunity in mice infected with L. major.

“…To explain their findings, the authors invoked the existence of two memory T cell subsets (40 -42): one subset has the characteristics of effector cells (effector memory cells), while the other acts as a reservoir of Agspecific T cells that have not committed to a specific cytokine profile and are referred to as nonpolarized (Tnp or central memory cells). These authors and others have shown that central memory cells are capable of becoming either T1 or T2 cells, depending on the conditions they encounter during reactivation (43)(44)(45). Consequently, the authors proposed that IL-12 is required to promote the development of T1 effector memory cells from central memory cells.…”

Section: Discussionmentioning

confidence: 99%

IL-12 Is Required for Induction but Not Maintenance of Protective, Memory Responses to Blastomyces dermatitidis: Implications for Vaccine Development in Immune-Deficient Hosts

Wüthrich

Warner²,

Klein

2005

Cellular immunity mediated by T lymphocytes, in particular CD4+ and CD8+ type 1 (T1) cells, is the main defense against pathogenic fungi. IL-12 initiates T1 cell development and cell-mediated immunity, but it is unclear whether IL-12 contributes to the maintenance of an antifungal T1 response. In this study, we addressed the role of IL-12 for vaccine-induced memory T cell development against experimental pulmonary blastomycosis. CD4+ T cells absolutely required IL-12 to control a live genetically engineered attenuated strain of Blastomyces dermatitidis given s.c. as a vaccine, whereas CD8+ T cells were significantly less dependent on IL-12. Despite differential dependency of T cell subsets on IL-12 during vaccination, neither subset acquired memory immunity in the absence of IL-12. In contrast, adoptive transfer of immune CD4 T cells from wild-type mice into IL-12−/− mice showed that CD4+ T1 memory cells sustained a T1 cytokine profile and remained protective over a period of 6 mo posttransfer. Similarly, memory CD8 cells elicited in IL-12−/− mice with killed yeast and transient rIL-12 treatment (during vaccination) remained durable and protective after animals were rested for 3 mo. In conclusion, these studies demonstrate that once CD4 and CD8 cells have acquired a protective T1 phenotype they no longer require the presence of IL-12 to maintain antifungal protective memory.