CD40 Engagement Enhances Antigen-Presenting Langerhans Cell Priming of IFN-γ-Producing CD4+ and CD8+ T Cells Independently of IL-12

Abstract

The delivery of CD40 signaling to APCs during T cell priming enhances many T cell-mediated immune responses. Although CD40 signaling up-regulates APC production of IL-12, the impact of this increased production on T cell priming is unclear. In this study an IL-12-independent T cell-mediated immune response, contact hypersensitivity (CHS), was used to further investigate the effect of CD40 ligation on the phenotypic development of Ag-specific CD4+ and CD8+ T cells. Normally, sensitization for CHS responses induces hapten-specific CD4+ T cells producing type 2 cytokines and CD8+ T cells producing IFN-γ. Treatment of mice with agonist anti-CD40 mAb during sensitization with the hapten 2,4-dinitrofluorobenzene resulted in CHS responses of increased magnitude and duration. These augmented responses in anti-CD40 Ab-treated mice correlated with increased numbers of hapten-specific CD4+ and CD8+ T cells producing IFN-γ in the skin draining lymph nodes. Identical results were observed using IL-12−/− mice, indicating that CD40 ligation promotes CHS responses and development of IFN-γ-producing CD4+ and CD8+ T cells in the absence of IL-12. Engagement of CD40 on hapten-presenting Langerhans cells (hpLC) up-regulated the expression of both class I and class II MHC and promoted hpLC migration into the T cell priming site. These results indicate that hpLC stimulated by CD40 ligation use a mechanism distinct from increased IL-12 production to promote Ag-specific T cell development to IFN-γ-producing cells.

Eosinophil differentiation in the bone marrow is inhibited by T cell–derived IFN-γ

“…31,32 Indeed, we found that this treatment up-regulated the expression of IFN-␥-responsive molecules, such as MHC-II and Sca-1 on a large proportion of bone marrow cells in WT mice, but not IFN-␥ Ϫ/Ϫ mice 3,15 (and data not shown). Importantly, anti-CD40-treated WT mice displayed a strong decrease in eosinophil numbers in both bone marrow and blood, whereas IFN-␥ Ϫ/Ϫ mice were not affected ( Figure 7A-C).…”

IFNγ induces monopoiesis and inhibits neutrophil development during inflammation

“…To test the effect of IFN␥ on the M:N ratio in a T-cell activation model that is not driven by transgenic CD70 expression, we injected WT and IFN␥ Ϫ/Ϫ mice with an agonistic anti-CD40 Ab, which increases the number of IFN␥-producing T cells. 20,32 We found that the M:N ratio increased in the BM of WT mice injected with anti-CD40, but not in IFN␥ Ϫ/Ϫ mice ( Figure 2D). In both experimental settings, we observed the same pattern of M:N ratio in the peripheral blood (data not shown).…”

In the Absence of CD154, Administration of Interleukin-12 Restores Th1 Responses but Not Protective Immunity toSchistosoma mansoni

“…Indeed, anti-CD40 MAb treatment of WT mice can induce strong Th1 responses in a variety of experimental models through both IL-12-dependent and -independent pathways (11,13,30,47). An alternative explanation was that the defective cellular response and the absence of protection in CD154 Ϫ/Ϫ mice was due to a failure of signaling through CD154 into the CD4 ϩ cell (7).…”

“…In this context, CD154 present on CD4 ϩ cells is a key molecule in the maturation of CD40-expressing APCs (41,49). APCs activated via the CD154/CD40 pathway upregulate other costimulatory molecules, such as CD80 and CD86, and inflammatory cytokines, such as IL-12, which together favor the development of Th1-type responses (6,7,13,23,40). This pathway is critical for the development of protective Th1-mediated immunity to the intracellular parasites Leishmania major and Toxoplasma gondii (5,43), although several other reports show that CD154 is not required for the development of protective immunity against pathogens, such as Mycobacterium tuberculosis, L. major, and Histoplasma histolytica (26,38,39,64).…”