Remodeling and Restraining Lung Tissue Damage Through the Regulation of Respiratory Immune Responses

Abstract

Tissue damage caused by various stimuli under certain conditions, such as biological and environmental cues, can actively induce systemic and/or local immune responses. Therefore, understanding the immunological perspective would be critical to not only regulating homeostasis of organs and tissues but also to restrict and remodel their damage. Lungs serve as one of the key immunological organs, and thus, in the present article, we focus on the innate and adaptive immune systems involved in remodeling and engineering lung tissue. Innate immune cells are known to react immediately to damage. Macrophages, one of the most widely studied types of innate immune cells, are known to be involved in tissue damage and remodeling, while type 2 innate lymphoid cells (ILC2s) have recently been revealed as an important cell type responsible for tissue remodeling. On the other hand, adaptive immune cells are also involved in damage control. In particular, resident memory T cells in the lung prevent prolonged disease that causes tissue damage. In this review, we first outlined the structure of the respiratory system with biological and environmental cues and the innate/adaptive immune responses in the lung. It is our hope that understanding an immunological perspective for tissue remodeling and damage control in the lung will be beneficial for stakeholders in this area.

Keywords: Adaptive immunity; Innate immunity; Innate lymphoid cell; Macrophages; Protective immune response; Respiratory system; T cell; Tissue damage; Tissue remodeling.

Fig. 1

Outline the structure and cellular composition of the lung. A depiction of the typical longitudinal section of lung with anatomic location for the proximal and distal airways. Respiratory epithelium consists of many distinct cell types, which serve as a defense barrier. A. The proximal airways are composed of ciliated cells, mucus-producing goblet cells, secretory club cells, tuft cells, undifferentiated basal cells and neuroendocrine cells. B. Alveolar type 1 (AT1) and type 2 (AT2) epithelial cells are make up the distal airways. Resident alveolar macrophages constantly scan the local microenvironment for potentially harmful pathogens

Fig. 2

Illustration of characteristic comparison between ILC and CD4⁺ T cell. ILCP differentiates into ILC1, ILC2, or ILC3, while ILCreg is derived directly from CHILP. By contrast, CD4⁺ T cells can be classified into Th1, Th2, Th17, Treg and Tfh. ILCs are described as innate counterparts to CD4⁺ T cells. The diagram depicts the overlapping roles of ILCs and CD4⁺ T cells with their subtypes. To note, ILC2 and Th2 are crucial for tissue homeostatic maintenance and remodeling in the lung. CHILP, common helper innate lymphoid progenitor; ILCP, innate lymphoid cell precursor; TSLP, thymic stromal lymphopoietin; APC, antigen presenting cell

Fig. 3

CD8⁺ T cell responses following respiratory pathogen infection. Upon the appropriate antigen presentation by APCs, naive CD8⁺ T cells become activated, as measured by the upregulation of activation markers, such as CD44, and the downregulation of the lymphoid homing receptor, CD62L. Then, frequency and numbers of activated CD8⁺ T cells expand in the lung. Complete viral clearance from the lung occurs at the same time as the peak of pulmonary CD8⁺ T cell expansion. After the peak expansion, contraction occurs to reduce the total number of CD8⁺ T cells followed by forming a memory population. Two memory CD8⁺ T cell populations are formed as following; TEM (CD62L^loCCR7^loIL-7Rα^loKLRG1^hi) that predominate within the lung but also capable of circulating, and TRM (CD62L^loCD69^hiCD103^hi) that represent a lung-resident population of memory CD8⁺ T cells. TEM, Effector memory T cell; TRM, Tissue resident memory T cell

Fig. 4

Innate and adaptive immune responses work in concert to eliminate the cues that damage the tissue. To promote optimal immune response against pathogen, the balance between innate and adaptive immunity must be achieved. When it works properly, the innate immune responses not only prevent the spread of pathogens through fast reactions to pathogens but also remodel damaged tissue. They could also initiate the adaptive immune response as the second line of defense. ILC2 among innate immune cells could be one of the most significant cells in tissue remodeling of lung tissue. CD8⁺ T cells play an important role in host defense against pathogens since they can eliminate the cause of damage. Not only that, Th2 cells among T cells are known to help tissue repair and regeneration. It is important to note that innate and adaptive immune responses must work together for the removal of harmful biological and environmental cues, the maintenance of healthy condition, and the repair of damaged tissue