The induction of type 1 immune responses (
interleukin [
IL]-12,
interferon [IFN]-gamma) has been shown to be important in mediating protection against many intracellular
infections including Histoplasma capsulatum. Costimulatory molecules such as
CD40 ligand (
CD40L) have been shown to be a central regulator of type 1 responses in vivo. To study the role of
CD40L in mediating protection against
infection with H. capsulatum, CD40L-deficient (
CD40L-/-) and
CD40L+/+ mice were infected with H. capsulatum and assessed for various parameters. After a lethal challenge of H. capsulatum,
CD40L-/- mice were not substantially different from
CD40L+/+ mice in terms of mortality, fungal burden, or production of IFN-gamma,
IL-12,
nitric oxide, or
tumor necrosis factor alpha. Moreover,
CD40L-/- mice treated with anti-IFN-gamma or anti-IL-12 at the time of
infection had accelerated mortality, providing further evidence that
IL-12 and IFN-gamma are produced in vivo in the absence of
CD40L. In addition,
CD40L-/- mice infected with a sublethal dose of H. capsulatum survived
infection, whereas all mice infected with the same dose and treated with anti-IFN-gamma had accelerated mortality, demonstrating that IFN-gamma but not
CD40L was essential for primary immunity to H. capsulatum
infection. Interestingly, depletion of either CD4+ or CD8+ T cells resulted in accelerated mortality in
CD40L-/- mice, suggesting a critical role for these cells in response to
infection. Finally,
CD40L-/- mice initially infected with a sublethal dose of H. capsulatum were protected from
secondary infection with a lethal dose of H. capsulatum, demonstrating that
CD40L is not required for the maintenance of memory immunity.