Immunization with Apoptotic Phagocytes Containing Histoplasma capsulatum Activates Functional CD8⁺T Cells To Protect against Histoplasmosis

Abstract

We have previously revealed the protective role of CD8 ؉ T cells in host defense against Histoplasma capsulatum in animals with CD4؉ T cell deficiency and demonstrated that sensitized CD8 ؉ T cells are restimulated in vitro by dendritic cells that have ingested apoptotic macrophage-associated Histoplasma antigen. Here we show that immunization with apoptotic phagocytes containing heat-killed Histoplasma efficiently activated functional CD8 ؉ T cells whose contribution was equal to that of CD4 ؉ T cells in protection against Histoplasma challenge. Inhibition of macrophage apoptosis due to inducible nitric oxide synthase (iNOS) deficiency or by caspase inhibitor treatment dampened the CD8 ؉ T cell but not the CD4 ؉ T cell response to pulmonary Histoplasma infection. In mice subcutaneously immunized with viable Histoplasma yeasts whose CD8 ؉ T cells are protective against Histoplasma challenge, there was heavy granulocyte and macrophage infiltration and the infiltrating cells became apoptotic. In mice subcutaneously immunized with carboxyfluorescein diacetate succinimidyl ester (CFSE)-labeled apoptotic macrophages containing heat-killed Histoplasma, the CFSE-labeled macrophage material was found to localize within dendritic cells in the draining lymph node. Moreover, depleting dendritic cells in immunized CD11c-DTR mice significantly reduced CD8 ؉ T cell activation. Taken together, our results revealed that phagocyte apoptosis in the Histoplasma-infected host is associated with CD8 ؉

Antifungal Therapy: New Advances in the Understanding and Treatment of Mycosis

“…Studies on vaccines protective against other fungi are still in the early pre-clinical phase (Fernandes et al, 2011; Hsieh et al, 2011; Edwards, 2012; Hole and Wormley, 2012; Shahid, 2016). …”

Adaptive Immunity to Fungi

“…þ cells in skin-draining lymph nodes and CD11c þ -dependent CTL-mediated protection against Histoplasma challenge (Hsieh et al 2011). Although these studies show that fungal Ags can be acquired and presented by resident DCs, the resident DC subpopulation(s) involved in vivo remain undefined.…”

“…These cytotoxic CD8 þ T cells are primed by DCs through the process of cross-presentation ( presentation of exogenous Ags on MHC class I). Furthermore, this lineage of T cells is critical for vaccine-induced immunity against A. fumigatus, B. dermatitidis, and H. capsulatum (Wuthrich et al 2003(Wuthrich et al , 2006Hsieh et al 2011;Carvalho et al 2012;Nanjappa et al 2012a). The most likely mechanisms through which memory CD8 þ T cells coordinate resolution of pathogen in these models is by the release of IFN-g and IL-17, and cytotoxic effects on infected cells.…”

Dendritic cell interactions withHistoplasmaandParacoccidioides

“…56 The fact that apoptotic peritoneal macrophages simply mixed with heat-killed Histoplasma before injection did not result in a strong CD8 or CD4 T cell response implies that in order for antigen presentation to efficiently occur, H. capsulatum antigens must be contained within apoptotic macrophages. 56 The study suggests that immunization with apoptotic peritoneal macrophages with ingested HK Hc activates both CD8 and CD4 T cells, providing protection against fungal infection. Hence, the function of apoptotic phagocytes as antigen donors and the resultant effective T cell response in combination with mechanism of cross-presentation can be applied to the development of fungal vaccines 56 as well as providing insight into disease pathogenesis.…”