Immunoregulation in Fungal Diseases

Abstract

This review addresses specific regulatory mechanisms involved in the host immune response to fungal organisms. We focus on key cells and regulatory pathways involved in these responses, including a brief overview of their broader function preceding a discussion of their specific relevance to fungal disease. Important cell types discussed include dendritic cells and regulatory T cells, with a focus on specific studies relating to their effects on immune responses to fungi. We highlight the interleukin-10, programmed cell death 1, and cytotoxic T lymphocyte-associated protein 4 signaling pathways and emphasize interrelationships between these pathways and the regulatory functions of dendritic cells and regulatory T cells. Throughout our discussion, we identify selected studies best illustrating the role of these cells and pathways in response to specific fungal pathogens to provide a contextual understanding of the tightly-controlled network of regulatory mechanisms critical to determining the outcome of exposure to fungal pathogens. Lastly, we discuss two unique phenomena relating to immunoregulation, protective tolerance and immune reactivation inflammatory syndrome. These two clinically-relevant conditions provide perspective as to the range of immunoregulatory mechanisms active in response to fungi.

Keywords: cytotoxic T lymphocyte-associated protein 4 (CTLA-4); dendritic cell (DC); fungi; immune reconstitution inflammatory syndrome (IRIS); immunoregulation; interleukin-10 (IL-10); programmed cell death 1 (PD-1); protective tolerance; regulatory T cell (Treg cell).

Figure 1

Immunity to Fungal Infections. Fungal infection (1) stimulates the arrival of monocytes at the site of infection (2), which subsequently mature into monocyte-derived dendritic cells (moDCs). Depending on local environmental host and pathogen factors, these moDCs can develop into either inflammatory DCs (inf-DCs; 3a) or immunomodulatory DCs (imo-DCs; 3b), which subsequently direct the immune response. Inf-DCs promote sterilizing immunity characterized by interferon gamma (IFNγ)-producing Th1 cells, interleukin (IL)-17-producing Th17 cells, and “classically activated” exudate macrophages (ExMs; 4a). Imo-DCs promote fungal persistence characterized by IL-10-producing Treg cells, IL-4-, IL-5, and IL-13-producing Th2 cells, and “alternatively-activated” exudate macrophages (4b).

Figure 2

Immunoregulatory Pathways. The development of immunomodulatory DCs leads to regulatory signaling via the IL-10, programmed cell death protein (PD)-1, and cytotoxic T lymphocyte-associated protein (CTLA)-4 pathways. These pathways in turn promote the development of Treg cells (as well as Th2 cells) and inhibit the development of Th1 and Th17 cells. The balance of these immunoregulatory pathways may determine whether persistent infection results in chronic immune-mediated tissue destruction (as occurs in Allergic Bronchopulmonary Mycosis) or Protective Tolerance.