Dendritic Cells in the Induction of Protective and Nonprotective Anticryptococcal Cell-Mediated Immune Responses

Bauman, Sean K.; Nichols, Kasie L.; Murphy, Juneann W.

doi:10.4049/jimmunol.165.1.158

Cited by 67 publications

(75 citation statements)

References 54 publications

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“…DCs are the primary antigen-presenting cells responsible for initiating a cellmediated immune response to MP (1). Therefore, we next examined whether DCs isolated from wild-type and MR KO mice differed in the capacity to bind and internalize MP.…”

Section: Resultsmentioning

confidence: 99%

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Role of the Mannose Receptor in a Murine Model ofCryptococcus neoformansInfection

et al. 2008

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Cryptococcus neoformans is an encapsulated fungal pathogen with a predilection to infect persons with suppressed T-cell function. Cryptococcal mannoproteins (MP) are highly mannosylated antigens which elicit T-cell responses in infected mice and in convalescent patients. Key to the immunogenicity of MP is its capacity to bind to the conserved mannose receptor (MR), CD206, on dendritic cells (DCs). To test the role of the MR in the immune response to C. neoformans, wild-type and MR knockout (MR KO) mice were compared by using in vivo and ex vivo models of cryptococcosis. Following a pulmonary challenge with C. neoformans, MR KO mice died significantly faster than wild-type mice and had higher lung fungal burdens after 4 weeks of infection. Uptake of MP was similar when DCs obtained from wild-type and MR KO mice were compared. Additionally, MP did not upregulate the maturation markers major histocompatibility complex class II, CD86, and CD40 in either wild-type or MR KO DCs. However, MP stimulated lymphoproliferation in CD4 ؉ T cells obtained from the peripheral lymph nodes of infected wild-type but not MR KO mice. These studies demonstrate a nonredundant role for the MR in the development of CD4 ؉ T-cell responses to MP and protection from C. neoformans.Cryptococcus neoformans is an opportunistic fungal pathogen which preferentially afflicts immunocompromised persons, particularly those with AIDS or lymphoid malignancies and recipients of immunosuppressive treatments for solid organ transplants (2). The primary site of infection is generally the lungs. While exposure is thought to be common, most immunocompetent persons are able to contain the infection. However, in the absence of effective CD4 ϩ T-cell responses, the organism can disseminate and eventually cross the blood-brain barrier to produce cryptococcal meningitis (18).The inverse correlation between CD4 ϩ T-cell function and the propensity to develop cryptococcosis has prompted investigators to search for antigens which drive the cell-mediated immune response. In this regard, a family of heavily mannosylated proteins, termed mannoproteins (MP), has been identified as immunodominant antigens in mouse models of cryptococcosis and in patients who have recovered from infection (1,16,26). MP possess serine-and threonine-rich C-terminal regions which serve as sites for extensive O-linked mannosylation. Additional mannosylation may be provided via N linkages (17). These areas of O-linked and N-linked mannosylation promote the recognition of MP by host receptors for mannose, in particular, the mannose receptor (MR, CD206) and dendritic cell (DC)-specific intercellular adhesion molecule 3 grabbing nonintegrin (CD209) (17,21). DCs are the main antigenpresenting cells responsible for the uptake, processing, and presentation of MP to CD4 ϩ T cells (21, 22). Blocking receptors for mannose with mannan or deglycosylating MP results in strongly diminished T-cell responses (21,22,32).The MR is a C-type lectin receptor which recognizes terminally mannosylated molecules (24...

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Section: Resultsmentioning

confidence: 99%

“…In this regard, a family of heavily mannosylated proteins, termed mannoproteins (MP), has been identified as immunodominant antigens in mouse models of cryptococcosis and in patients who have recovered from infection (1,16,26). MP possess serine-and threonine-rich C-terminal regions which serve as sites for extensive O-linked mannosylation.…”

mentioning

confidence: 99%

Role of the Mannose Receptor in a Murine Model ofCryptococcus neoformansInfection

et al. 2008

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“…Immune responses generated to live pathogens have been often found to be quantitatively and qualitatively different from responses elicited by challenge with heat-inactivated pathogens (1,24,32,43). Indeed, heat-inactivated vaccines often result in nonprotective immunity (32,52).…”

Section: Discussionmentioning

confidence: 99%

Distinct CD4⁺-T-Cell Responses to Live and Heat-InactivatedAspergillus fumigatusConidia

et al. 2005

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Aspergillus fumigatus is an important fungal pathogen that causes invasive pulmonary disease in immunocompromised hosts. Respiratory exposure to A. fumigatus spores also causes allergic bronchopulmonary aspergillosis, a Th2 CD4؉ -T-cell-mediated disease that accompanies asthma. The microbial factors that influence the differentiation of A. fumigatus-specific CD4 ؉ T lymphocytes into Th1 versus Th2 cells remain incompletely defined. We therefore examined CD4؉ -T-cell responses of immunologically intact mice to intratracheal challenge with live or heat-inactivated A. fumigatus spores. Live but not heat-inactivated fungal spores resulted in recruitment of gamma interferon (IFN-␥)-producing, fungus-specific CD4؉ T cells to lung airways, achieving A. fumigatus-specific frequencies exceeding 5% of total CD4 ؉ T cells. While heat-inactivated spores did not induce detectable levels of IFN-␥-producing, A. fumigatus-specific CD4 ؉ T cells in the airways, they did prime CD4؉ T-cell responses in draining lymph nodes that produced greater amounts of interleukin 4 (IL-4) and IL-13 than T cells responding to live conidia. While immunization with live fungal spores induced antibody responses, we found a marked decrease in isotype-switched, A. fumigatus-specific antibodies in sera of mice following immunization with heat-inactivated spores. Our studies demonstrate that robust Th1 T-cell and humoral responses are restricted to challenge with fungal spores that have the potential to germinate and cause invasive infection. How the adaptive immune system distinguishes between metabolically active and inactive fungal spores remains an important question.

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“…Conversely, DC of the myeloid-related lineage express high levels of CD11b but no CD8␣ (19,23). As done by others (3,24), we have applied the designations "MDC" to the CD11b high CD8␣ Ϫ myeloid-related DC subset and "LDC" to the CD11b low/Ϫ CD8␣ ϩ lymphoid-related DC subset. MDC are thought to originate from a common DC and myeloid cell precursor and constitute the majority of DC in lymphoid and nonlymphoid tissues (30); LDC appear to develop from a lymphoid progenitor population (28), although recent work suggests that intrathymic T cells and lymphoid-related DC arise from different precursors (25).…”

Section: Dendritic Cells Are Pivotal Antigen-presenting Cells For Genmentioning

confidence: 99%

Induction of Polyomavirus-Specific CD8⁺T Lymphocytes by Distinct Dendritic Cell Subpopulations

Drake

Shawver

Hadley

et al. 2001

J Virol

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Dendritic cells are pivotal antigen-presenting cells for generating adaptive T-cell responses. Here, we show that dendritic cells belonging to either the myeloid-related or lymphoid-related subset are permissive for infection by mouse polyomavirus and, when loaded with a peptide corresponding to the immunodominant anti-polyomavirus CD8 ؉ T-cell epitope or infected by polyomavirus, are each capable of driving expansion of primary polyomavirus-specific CD8 ؉ T-cell responses in vivo.

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Dendritic Cells in the Induction of Protective and Nonprotective Anticryptococcal Cell-Mediated Immune Responses

Cited by 67 publications

References 54 publications

Role of the Mannose Receptor in a Murine Model ofCryptococcus neoformansInfection

Role of the Mannose Receptor in a Murine Model ofCryptococcus neoformansInfection

Distinct CD4⁺-T-Cell Responses to Live and Heat-InactivatedAspergillus fumigatusConidia

Induction of Polyomavirus-Specific CD8⁺T Lymphocytes by Distinct Dendritic Cell Subpopulations

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Dendritic Cells in the Induction of Protective and Nonprotective Anticryptococcal Cell-Mediated Immune Responses

Cited by 67 publications

References 54 publications

Role of the Mannose Receptor in a Murine Model ofCryptococcus neoformansInfection

Role of the Mannose Receptor in a Murine Model ofCryptococcus neoformansInfection

Distinct CD4+-T-Cell Responses to Live and Heat-InactivatedAspergillus fumigatusConidia

Induction of Polyomavirus-Specific CD8+T Lymphocytes by Distinct Dendritic Cell Subpopulations

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Distinct CD4⁺-T-Cell Responses to Live and Heat-InactivatedAspergillus fumigatusConidia

Induction of Polyomavirus-Specific CD8⁺T Lymphocytes by Distinct Dendritic Cell Subpopulations