Roles for CD40, B7 and major histocompatibility complex in induction of enhanced immunity by cryptococcal polysaccharide‐pulsed antigen‐presenting cells

Abstract

SUMMARYImmunization of mice with activated antigen-presenting cells (APC) pulsed ex vivo with cryptococcal capsular polysaccharide, a glucuronoxylomannan (GXM-APC) results in prolongation of survival and delayed-type hypersensitivity (DTH) responsiveness following infection with Cryptococcus neoformans (NU-2). GXM-APC has both non-specific and GXM-specific effects that influence the immune responses that develop in mice after infection with NU-2. Type 1 cytokine responses are augmented after immunization with APC alone, while GXM must be present for the vaccine to influence survival and DTH reactions. This investigation evaluated the role that major histocompatibility complex (MHC) and co-stimulatory molecules play in the non-specific and GXM-specific responses induced by GXM-APC. APC from CD40 knockout mice were as effective as wild-type APC for the induction of non-specific and GXM-specific responses. Blocking activity of B7-1 and B7-2 by treatment of immunized mice with monoclonal antibodies specific for these molecules just before and for 6 days following GXM-APC immunization decreased the splenic interferon-g response of mice subsequently infected with NU-2, but only in mice that were treated with both antibodies. These antibody treatments had no effect on DTH reactivity in similarly treated animals. MHC class I molecules were not involved in the antigen non-specific or GXM-specific activities of the vaccine. MHC class II molecules were not required for augmentation of type 1 cytokine responses but were needed for induction of the GXM-specific response that regulates the expression of DTH reactivity. This investigation has shown that an MHC class II-restricted, GXMspecific response is responsible for altering DTH responsiveness which is the correlate of immunity in this model.

Paradoxical Immune Responses in Non-HIV Cryptococcal Meningitis

“…We identified poor proportional monocyte recruitment to the circulating pool of the CSF cells and a predominant non-protective M2 response in most of the autopsy specimens, as well as an inability to phagocytose the fungus in situ. This is consistent with our recent data demonstrating the presence of a STAT5 phosphorylation-blocking GM-CSF autoantibody in a subset of patients with cryptococcal disease [ 25 , 60 ] and suggest that future targeted studies should focus on the mechanistic assessment of cells of myeloid lineage, including evaluation of phagocytosis [ 61 ], oxidative burst [ 62 ]and antigen processing [ 63 ] important to cryptococcal defense. In conclusion, the present study suggests that an ineffective macrophage response in the setting of intact T-cell activation has the potential to cause increased susceptibility of the patient to the fungus and severe CNS disease after initiation of effective anti-fungal therapy.…”

Chapter 4 The Capsule of the Fungal Pathogen Cryptococcus neoformans

“…The authors concluded that during this process, GXM-dependent and GXM-independent effects occurred. GXM-specific effects were dependent on MHC class II, while GXM independent effects required B7-1 and B7-2 molecules (Blackstock, 2003). …”

Role of Interleukin-4 in Resistance toCryptococcus neoformansInfection

“…DTH analyses were included in our study because the DTH reaction is known to correlate with protective immunity when combined with mononuclear infiltrates and elevated IFN-␥ levels in DTH reaction sites (18). In addition, high IFN-␥ levels without DTH responses do not provide protective immunity to mice infected with C. neoformans (19,20). Results of these studies revealed that IL-4 was needed for development of strong DTH responses after primary infection with both cryptococcal isolates, and IL-4 deficiency did not increase survival of mice undergoing a primary infection with either isolate.…”