CD4⁺T Cell Regulation of Antibodies Cross-Reactive with Fungal Cell Wall-Associated Carbohydrates afterPneumocystis murinaInfection

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 β-glucan and signal at Fcγ 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 β-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 β-glucan or chitosan/chitin in the serum or mucosa after challenge. Notably, lung mucosal quantities of IgA cross-reactive with β-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 β, 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 β-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.

Germline IgM predicts T cell immunity to Pneumocystis

“…Previous work has shown that conserved natural IgM antibodies with carbohydrate specificities can mediate innate and adaptive immunity against Pneumocystis (11,12). Given that Pneumocystis clearance is mediated by class II restricted CD4+ T cells, we hypothesized that IgM with protein specificities may predict subsequent class II dependent antigens.…”

Targeting β-glucans, vital components of the Pneumocystis cell wall

“…Moreover, despite CD4+ T-cell depletion, IgM levels increased significantly. Thus, an immune response against Pneumocystis β-glucan might occur under conditions of CD4+ T cell-related immunodeficiency via differential CD4+ T cell-dependent regulation of mucosal antibody responses ( 50 ).…”