B7-1 and B7-2 Have Overlapping, Critical Roles in Immunoglobulin Class Switching and Germinal Center Formation

274

270

Peripheral blood monocytes are a population of circulating mononuclear phagocytes that harbor potential to differentiate into macrophages and dendritic cells. As in humans, monocytes in the mouse comprise two phenotypically distinct subsets that are Gr1 high CX 3 CR1 int and Gr1 low CX 3 CR1 high , respectively. The question remains whether these populations contribute differentially to the generation of peripheral mononuclear phagocytes. In this study, we track the fate of adoptively transferred, fractionated monocyte subsets in the lung of recipient mice. We show that under inflammatory and noninflammatory conditions, both monocyte subsets give rise to pulmonary dendritic cells. In contrast, under the conditions studied, only Gr1 low CX 3 CR1 high monocytes, but not Gr1 high CX 3 CR1 int cells, had the potential to differentiate into lung macrophages. However, Gr1 high CX 3 CR1 int monocytes could acquire this potential upon conversion into Gr1 low CX 3 CR1 high cells. Our results therefore indicate an intrinsic dichotomy in the differentiation potential of the two main blood monocyte subsets.

Section: Micementioning

confidence: 99%

Section: Monocyte-derived Lung DC Can Prime Naive T Cellsmentioning

confidence: 99%

Distinct Differentiation Potential of Blood Monocyte Subsets in the Lung

Landsman

Varol

Jung

2007

274

270

“…CD80 Ϫ/Ϫ and CD86 Ϫ/Ϫ mice on a Sv129 background were generated as previously described (33). CD80 Ϫ/Ϫ and CD86 Ϫ/Ϫ mice were bred nine times onto the BALB/c (H-2 d ) background.…”

Section: Micementioning

confidence: 99%

An Important Role of CD80/CD86-CTLA-4 Signaling during Photocarcinogenesis in Mice

Loser

Scherer

Krummen

et al. 2005

Although previous studies have shown that altered B7 costimulation plays a critical role in UV irradiation-induced regulation of immunity, the individual roles of the B7 receptors (CD28 and CTLA-4) or the B7 family members (CD80 and CD86) have not been explored. Thus, we investigated CTLA-4 signaling during photocarcinogenesis of chronically UV-B-exposed mice using an antagonistic anti-CTLA-4 Ab. Anti-CTLA-4-treated mice developed significantly fewer UV-induced tumors. Moreover, anti-CTLA-4 treatment induced long-lasting protective immunity because progressively growing UV tumors inoculated into anti-CTLA-4- and UV-treated mice that had not developed tumors were rejected. Next, we used mice deficient for CD80, CD86, or both in photocarcinogenesis studies to assess the relative contributions of these CTLA-4 ligands. Double-deficient mice showed significantly reduced UV-induced skin tumor development, whereas CD86−/− mice produced skin cancer earlier compared with CD80−/− and control mice. The growth of UV-induced tumors appears to be controlled by UV-induced suppressor T cells, because CD80−/−/CD86−/− mice had strongly reduced numbers of UV-induced CD4+CD25+ suppressor T cells. In vitro, CTLA-4 blockade inhibited the suppressor activity of UV-induced CD4+CD25+ T cells, suggesting that reduced photocarcinogenesis might be due to decreased numbers or function of suppressor T cells. Together, these data indicate that blocking CD80/86-CTLA-4 signaling induced immune protection against the development of UV-induced skin tumors. Furthermore, CD86-mediated costimulation appears to play a more critical role in the protection against photocarcinogenesis than CD80.

“…B6 CD40L KO, B6 CD28 KO, BALB CD28 KO, and BALB CD40 KO mice were obtained from The Jackson Laboratory (Bar Harbor, ME) and were maintained at Bioqual. BALB mice deficient in both B7-1-deficient and B7-2 (BALB B7 double-KO (DKO)) were a generous gift from A. Sharpe (10). CB6F 1 CD28 ϩ/Ϫ and CB6F 1 CD28 Ϫ/Ϫ mice were generated by crossing B6 CD28 ϩ/ϩ ϫ B6 CD28 Ϫ/Ϫ mice and then crossing B6 CD28 ϩ/Ϫ progeny to BALB CD28 Ϫ/Ϫ mice.…”

Section: Micementioning

confidence: 99%

CD40 Ligand Functions Non-Cell Autonomously to Promote Deletion of Self-Reactive Thymocytes

Williams

Sharrow

Adams

et al. 2002

CD40 ligand (CD40L)-deficient mice have been shown to have a defect in negative selection of self-reactive T cells during thymic development. However, the mechanism by which CD40L promotes deletion of autoreactive thymocytes has not yet been elucidated. We have studied negative selection in response to endogenous superantigens in CD40L-deficient mice and, consistent with previous reports, have found a defect in negative selection in these mice. To test the requirement for expression of CD40L on T cells undergoing negative selection, we have generated chimeric mice in which CD40L wild-type and CD40L-deficient thymocytes coexist. We find that both CD40L wild-type and CD40L-deficient thymocytes undergo equivalent and efficient negative selection when these populations coexist in chimeric mice. These results indicate that CD40L can function in a non-cell-autonomous manner during negative selection. Deletion of superantigen-reactive thymocytes was normal in B7-1/B7-2 double-knockout mice, indicating that CD40-CD40L-dependent negative selection is not solely mediated by B7 up-regulation and facilitation of B7-dependent T cell signaling. Finally, although the absence of CD40-CD40L interactions impairs negative selection of autoreactive CD4+ and CD8+ cells during thymic development, we find that self-reactive T cells are deleted in the mature CD4+ population through a CD40L-independent pathway.