Helper T-cell responses and pulmonary fungal infections

Abstract

The mucosal surface of the respiratory tract encounters microbes, such as fungal particles, with every inhaled breath. When pathogenic fungi breach the physical barrier and innate immune system within the lung to establish an infection, adaptive immunity is engaged, often in the form of helper CD4 T-cell responses. Type 1 responses, characterized by interferon-γ production from CD4 cells, promote clearance of Histoplasma capsulatum and Cryptococcus neoformans infection. Likewise, interleukin-17A (IL-17A) production from Th17 cells promotes immunity to Blastomyces dermatitidis and Coccidioides species infection by recruiting neutrophils. In contrast the development of T helper type 2 responses, characterized by IL-5 production from T cells and eosinophil influx into the lungs, drives allergic bronchopulmonary aspergillosis and poor outcomes during C. neoformans infection. Experimental vaccines against several endemic mycoses, including Histoplasma capsulatum, Coccidioides, Cryptococcus and Blastomyces dermatitidis, induce protective T-cell responses and foreshadow the development of vaccines against pulmonary fungal infections for use in humans. Additionally, recent work using antifungal T cells as immunotherapy to protect immune-compromised patients from opportunist fungal infections also shows great promise. This review covers the role of T-cell responses in driving protection and pathology in response to pulmonary fungal infections, and highlights promising therapeutic applications of antifungal T cells.

Keywords: T cell; adaptive immunity; fungal infection; lung; mucosal immunity.

Figure 1

T‐cell responses to pulmonary fungal infections. Left column: Type 1 responses, characterized by interferon‐γ (IFN‐γ) production from CD4 cells and Type 1/classically activated macrophages, mediate antifungal immunity to Histoplasma capsulatum and Cryptococcus neoformans infection. Centreal column: Eosinophil and alternatively activated macrophages supported by interleukin‐4 (IL‐4), IL‐5 and IL‐13 production from T cells protect against Pneumocystis jiroveci infection and drive pathology during allergic bronchopulmonary aspergillosis (ABPA). Right column: Host immunity to Blastomyces dermatitidis, Aspergillus fumigatus and Coccidioides species is mediated in part by T helper type 17 cells by IL‐17A and neutrophil‐dependent mechanisms.