CD4 T Cell regulation of antibodies cross-reactive with fungal cell wall-associated carbohydrates after Pneumocystis murina infection

Abstract

Pneumocystis pneumonia is a life-threatening opportunistic fungal infection observed in individuals with severe immunodeficiencies, such as AIDS. Molecules with the ability to bind -glucan and signal at Fc receptors enhance defense against Pneumocystis f. sp. murina, though it is unclear whether antibodies reactive with fungal cell wall carbohydrates are induced during Pneumocystis infection. We observed that systemic and lung mucosal immunoglobulins cross-reactive with -glucan and chitosan/chitin are generated after Pneumocystis infection, with increased quantities within the lung mucosal fluid after challenge. While IgG responses against Pneumocystis protein antigens are markedly CD4 T cell dependent, CD4 T cell depletion did not impact quantities of IgG cross-reactive with -glucan or chitosan/chitin in the serum or mucosa after challenge. Notably, lung mucosal quantities of IgA cross-reactive with -glucan or chitosan/ chitin are decreased in the setting of CD4 T cell deficiency, occurring in the setting of concurrent reduced quantities of active transforming growth factor , while mucosal IgM is significantly increased in the setting of CD4 T cell deficiency. Interleukin-21 receptor deficiency does not lead to reduction in mucosal IgA reactive with fungal carbohydrate antigens after Pneumocystis challenge. These studies demonstrate differential CD4 T cell-dependent regulation of mucosal antibody responses against -glucan and chitosan/chitin after Pneumocystis challenge, suggesting that different B cell subsets may be responsible for the generation of these antibody responses, and suggest a potential immune response against fungi that may be operative in the setting of CD4 T cell-related immunodeficiency.