CD4(+) T-cell subsets and host defense in the lung

Abstract

CD4(+) T-helper subsets are lineages of T cells that have effector function in the lung and control critical aspects of lung immunity. Depletion of these cells experimentally or by drugs or human immunodeficiency virus (HIV) infection in humans leads to the development of opportunistic infections as well as increased rates of bacteremia with certain bacterial pneumonias. Recently, it has been proposed that CD4(+) T-cell subsets may also be excellent targets for mucosal vaccination to prevent pulmonary infections in susceptible hosts. Here, we review recent findings that increase our understanding of T-cell subsets and their effector cytokines in the context of pulmonary infection.

Figure 1

CD 4 ⁺ T‐helper cell differentiation. Antigen is presented by dendritic cells (DCs) by class II major histocompatibility complex (MHC) to naive CD4⁺ Th0 cells. Full T‐cell activation requires a second signal consisting of the upregulation and expression of costimulatory molecules such as inducible costimulatory ligand (ICOSL), CD28, and cytotoxic T‐lymphocyte antigen‐4 (CTLA‐4). T‐cell differentiation is instructed by cytokine/growth factor signals. T‐bet can be activated by STAT1 as well as bind to the IFNγ locus followed by induction of IL‐12βR2. IL‐12 activates STAT4, which can further drive Th1 development. IFNγ can act in an autocrine manner to further augment Th1 differentiation. IL‐4 induces Gata3, which further induces IL‐4 and supports the differentiation of Th2 cells. Th2 cells produce IL‐4, IL‐5, and IL‐13 as their effector cytokines. TGFβ and IL‐6 can induce RORγt expression as well as activation of STAT3. This leads to induction of the IL‐23 receptor, rendering these cells responsive to IL‐23, which is required for terminal differentiation of Th17 cells. Th17 cells produce the cytokines IL‐17/IL‐17F, IL‐22, IL‐21. IL‐21 can act in an autocrine fashion to further the differentiation of the Th17 lineage.

Figure 2

Th2 cells and immunity at the mucosa. Allergen parasites or helminthic infection can induce TSLP and IL‐25 in the lung epithelium. These cytokines can drive early IL‐4 production leading to the differentiation of Th2 cells. IL‐4 and IL‐13 can drive the induction of IgE as well as stimulate epithelial cells to increase mucous production. IL‐5 is a critical regulator of eosinophilopoiesis. Binding of IgE to FcRε on mast cells leads to their degranulation and release of chymases, tryptases, and histamines.

Figure 3

Th17 cytokines in mucosal immunity. Many infections, including those caused by fungi and bacteria, can activate dendritic cells and macrophages to produce interleukin‐6 (IL‐6), IL‐23, and IL‐1β. IL‐23 and IL‐1β can drive IL‐17 production by both innate lymphoid cells and γδ T cells. Differentiation of Th17 cells requires TGFβ, and a critical mechanism of activation of TGFβ in the lung is through the activation of this growth factor by αv integrins. IL‐17 and IL‐22 can signal to the epithelium to augment G‐CSF as well as ligands for CXCR2 that mediate the recruitment of neutrophils. These two cytokines also induce the expression of anti‐microbial proteins such as lipocalin‐2 and β‐defensins. IL‐22 can also augment epithelial repair. After vaccination, Th17 cells through the production of IL‐17 can also induce ligands for CXCR3 that increase the recruitment of IFNγ‐producing Th1 cells, which can also help control intracellular pathogen growth.