Eosinophils elicit proliferation of naive and fungal-specific cells in vivo so enhancing a T helper type 1 cytokine profile in favour of a protective immune response against Cryptococcus neoformans infection

Abstract

Summary Experimental Cryptococcus neoformans infection in rats has been shown to have similarities with human cryptococcosis, because as in healthy humans, rats can effectively contain cryptococcal infection. Moreover, it has been shown that eosinophils are components of the immune response to C. neoformans infections. In a previous in vitro study, we demonstrated that rat peritoneal eosinophils phagocytose opsonized live yeasts of C. neoformans, thereby triggering their activation, as indicated by the up‐regulation of MHC and co‐stimulatory molecules and the increase in interleukin‐12, tumour necrosis factor‐α and interferon‐γ production. Furthermore, this work demonstrated that C. neoformans‐specific CD4+ and CD8+ T lymphocytes cultured with these activated C. neoformans‐pulsed eosinophils proliferated, and produced important amounts of T helper type 1 (Th1) cytokines in the absence of Th2 cytokine synthesis. In the present in vivo study, we have shown that C. neoformans‐pulsed eosinophils are also able to migrate into lymphoid organs to present C. neoformans antigens, thereby priming naive and re‐stimulating infected rats to induce T‐cell and B‐cell responses against infection with the fungus. Furthermore, the antigen‐specific immune response induced by C. neoformans‐pulsed eosinophils, which is characterized by the development of a Th1 microenvironment with increased levels of NO synthesis and C. neoformans‐specific immunoglobulin production, was demonstrated to be able to protect rats against subsequent infection with fungus. In summary, the present work demonstrates that eosinophils act as antigen‐presenting cells for the fungal antigen, hence initiating and modulating a C. neoformans‐specific immune response. Finally, we suggest that C. neoformans‐loaded eosinophils might participate in the protective immune response against these fungi.

The Regulatory Function of Eosinophils

“…Antigen (OVA)-loaded and GM-CSF–treated eosinophils, when instilled intratracheally, promote the proliferation of adoptively transferred OVA-specific T-cell clones, which is accompanied by T-cell CD69 upregulation and IL-4 production and T cell/eosinophil co-localization in the draining lymph node (19). In a murine allergic asthma model, peripheral eosinophil recruitment into the lymph node is required for antigen-specific T-cell proliferation in situ (20), In addition to the pulmonary system, murine studies have also demonstrated the antigen-presenting capacity of eosinophils in threadworm (21) and fungus infections (22). Moreover, considering that eosinophils are potent cytokine producers and regulators of humoral immunity and are usually isolated from a population rich in professional APCs, the direct evidence for the physical T cell/eosinophil interaction (e.g.…”

Impact of Surfactant Protein D, Interleukin-5, and Eosinophilia on Cryptococcosis

“…Along with the widely published fact that eosinophilia has often been associated with ineffective immune responses against C. neoformans, it has been shown that eosinophils bind C. neoformans in the presence of opsonizing antibodies (41), that late-phase C. neoformans-induced pulmonary eosinophilia is IL-5 dependent (8), and that eosinophils have C. neoformans-derived antigen-presenting capabilities (42,43). Recently eosinophils were found to be important producers of IL-4 and thus are contributors to nonprotective Th2 responses (44).…”

Vaccines and Protective Immune Memory against Cryptococcosis

“…13,14) It was shown that eosinophils (Eos) can also be used for immunization against cryptococcosis in a rat model. 78,79) Eos can phagocytize opsonized cryptococcal cells and present antigens to T cells in a major histocompatibility complex (MHC)-dependent manner. 78) The transfer of cryptococcal cell-pulsed Eos (Cn-pulsed Eos) significantly decreased the fungal burden after challenge with C. neoformans.…”

“…78,79) Eos can phagocytize opsonized cryptococcal cells and present antigens to T cells in a major histocompatibility complex (MHC)-dependent manner. 78) The transfer of cryptococcal cell-pulsed Eos (Cn-pulsed Eos) significantly decreased the fungal burden after challenge with C. neoformans. 79) Interestingly, Cn-pulsed Eos promoted the proliferation of C. neoformans-specific T cells producing IFN-γ but not interleukin (IL)-4.…”

“…79) Interestingly, Cn-pulsed Eos promoted the proliferation of C. neoformans-specific T cells producing IFN-γ but not interleukin (IL)-4. 78) Although there is an advantage that these approaches can induce protective CMI, ACT-based vaccines will not be immediately applied in the clinical setting due to the cost- Table 1. It was demonstrated that DCs and Eos could be used for ACT to induce protective CMI.…”