An early imbalance of interleukin 12 influences the adjuvant effect of mannoproteins of Cryptococcus neoformans.
Mannoprotein from Cryptococcus neoformans induces protective response against a lethal challenge with this fungus or with Candida albicans. This phenomenon is largely related to early production of interleukin 12 (IL-12) and induction of T helper 1 response. Our study assesses whether the early absence of this critical cytokine could account for the incomplete activation of cellular response and whether the immune system compensates this imbalance. The results show that the neutralization of early IL-12 enhanced IL-18 production but decreased IFN-gamma secretion and IL-12R expression by splenic CD4 T cells. In contrast, IL-18R was not augmented despite an increase in IL-18 production. The co-stimulatory pathway was partially dysregulated because splenic macrophages showed unmodified B7-2, and a decrease of B7-1 expression. This dysregulation led to incomplete proliferative response of T cells in response to Cryptococcus neoformans and to increased fungal load in the brain 21 days post infection. The inability to dispose early IL-12, forced the immune system to compensate the imbalance and produced a series of long-lasting dysregulations involving the co-stimulatory pathway and T cell activation.
Microbiology Section, Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Perugia, Italy.
Donatella
D
Pietrella
Patrizia
P
Lupo
Francesco
F
Bistoni
Anna
A
Vecchiarelli
D000276:Adjuvants, Immunologic; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D018122:B7-1 Antigen / Q000378:metabolism; D051940:B7-2 Antigen; D001921:Brain / Q000382:microbiology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D015169:Colony Count, Microbial; D003453:Cryptococcosis / Q000276:immunology / Q000382:microbiology; D003455:Cryptococcus neoformans / Q000276:immunology* / Q000378:metabolism*; D004195:Disease Models, Animal; D007371:Interferon-gamma / Q000378:metabolism; D018664:Interleukin-12 / Q000276:immunology* / Q000378:metabolism*; D020382:Interleukin-18 / Q000378:metabolism; D053727:Interleukin-18 Receptor alpha Subunit; D008213:Lymphocyte Activation; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D018123:Receptors, Interleukin / Q000378:metabolism; D053707:Receptors, Interleukin-12; D053724:Receptors, Interleukin-18; D018417:Th1 Cells / Q000276:immunology
D000276:Adjuvants, Immunologic; D015703:Antigens, CD; D018122:B7-1 Antigen; D051940:B7-2 Antigen; C497965:Cd86 protein, mouse; C508573:Il18r1 protein, mouse; D020382:Interleukin-18; D053727:Interleukin-18 Receptor alpha Subunit; D008562:Membrane Glycoproteins; D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; D053724:Receptors, Interleukin-18; C025363:mannoproteins; D018664:Interleukin-12; D007371:Interferon-gamma