Protective and Memory Immunity toHistoplasma capsulatumin the Absence of IL-10

Abstract

We determined whether the absence of IL-10 in mice influenced protective and memory immunity to Histoplasma capsulatum. IL-10−/− mice cleared primary and secondary infection more rapidly than wild-type controls. Administration of mAb to TNF-α or IFN-γ, but not GM-CSF, abrogated protection in naive IL-10−/− mice; mAb toTNF-α, but not IFN-γ or GM-CSF, subverted protective immunity in secondary histoplasmosis. The inflammatory cell composition in IL-10−/− mice was altered in those given mAb to IFN-γ or TNF-α. More Gr-1+ and Mac-3+ cells were present in lungs of IL-10−/− mice given mAb to IFN-γ, and treatment with mAb to TNF-α sharply reduced the number of CD8+ cells in lungs of IL-10−/− mice. We ascertained whether the lack of IL-10 modulated memory T cell generation or the protective function of cells. The percentage of CD3+, CD44high, CD62low, and IFN-γ+ cells in IL-10−/− mice was higher than that of wild-type at day 7 but not day 21 or 49 after immunization. Fewer splenocytes from immunized IL-10−/− mice were required to mediate protection upon adoptive transfer into infected TCR αβ−/− mice. Hence, deficiency of IL-10 confers a salutary effect on the course of histoplasmosis, and the beneficial effects of IL-10 deficiency require endogenous TNF-α and/or IFN-γ. Memory cell generation was transiently increased in IL-10−/− mice, but the protective function conferred by cells from these mice following immunization is strikingly more vigorous than that of wild-type.

Monoclonal Antibodies to Heat Shock Protein 60 Alter the Pathogenesis ofHistoplasma capsulatum

“…In our studies, MAbs that were protective induced higher levels of IL-2 and IL-12 and a trend toward higher levels of IFN-␥ by day 7, all of which subsequently decreased as the disease resolved. These MAbs also reduced the levels of IL-4 and IL-10, which correlates with previous findings that decreases in IL-4 and IL-10 levels, along with increases in IFN-␥ and TNF-␣ levels, are essential for controlling infection (12,34). The increased number of CFU and pronounced Th-2 cytokine expression are consistent with the accelerated deaths of animals compared to controls observed in survival experiments.…”

Vaccination with Heat Shock Protein 60 Induces a Protective Immune Response against ExperimentalParacoccidioides brasiliensisPulmonary Infection

“…Differences did emerge between H. capsulatum HSP60 and PbHSP60. With the former, IL-10 was elevated and found to be essential for vaccine efficacy during the inductive phase (18) but was inhibitory of natural immunity (19). On the other hand, IL-10 was not released by PbHSP60-exposed splenocytes, strongly suggesting that it does not play a role in vaccine-associated immunity.…”

A Deficiency in Gamma Interferon or Interleukin-10 Modulates T-Cell-Dependent Responses to Heat Shock Protein 60 fromHistoplasma capsulatum

“…The absence of IL-10 greatly influenced the generation of Th1 cells, as has been observed previously. In mice, the absence of IL-10 or the blockade of its cognate receptor enhances the protective immune response to Leishmania donovani, Plasmodium spp., Listeria monocytogenes, Coccidioides immitis, Mycobacterium spp., and H. capsulatum (10,13,20,23,24,28). Despite the pronounced skewing of the immune response to a Th1 phenotype, neither polyclonal nor monoclonal cells from IL- were examined or whether the examination was restricted to V␤8.1/8.2 ϩ cells.…”