Legend of the Sentinels: Development of Lung Resident Memory T Cells and Their Roles in Diseases

Abstract

SARS-CoV-2 is wreaking havoc around the world. To get the world back on track, hundreds of vaccines are under development. A deeper understanding of how the immune system responds to SARS-CoV-2 re-infection will certainly help. Studies have highlighted various aspects of T cell response in resolving acute infection and preventing re-infections. Lung resident memory T (T_RM) cells are sentinels in the secondary immune response. They are mostly differentiated from effector T cells, construct specific niches and stay permanently in lung tissues. If the infection recurs, locally activated lung T_RM cells can elicit rapid immune response against invading pathogens. In addition, they can significantly limit tumor growth or lead to pathologic immune responses. Vaccines targeting T_RM cells are under development, with the hope to induce stable and highly reactive lung T_RM cells through mucosal administration or "prime-and-pull" strategy. In this review, we will summarize recent advances in lung T_RM cell generation and maintenance, explore their roles in different diseases and discuss how these cells may guide the development of future vaccines targeting infectious disease, cancer, and pathologic immune response.

Keywords: asthma; cancer; infection; lung; tissue-resident memory T cells; vaccine.

Figure 1

Generation and maintenance of lung T_RM cells. During the activated phase of infection, dendritic cells present antigens to activate naïve T cells in the lymph nodes. These cells turn into effector T cells and up-regulate surface marker CXCR3, CXCR6, CCR5, which guide them into inflammatory tissues. After entering lung tissue, part of effector T cells is regulated by environmental signals including cytokines such as TGF-β and cognate antigens, and differentiate into lung T_RM cells. The rest of the effector T cells undergoes cell death or egress out of the lung. Compared with Teff cells, lung T_RM cells manipulate multiple surface markers and transcription factors that facilitate cell maintenance and survival.

Figure 2

An abstract figure of the role of T_RM cells in various lung diseases. Lung T_RM cells can: (A) rapidly respond towards invasive pathogens during re-infection, (B) cause pathologic immune response after overactivated by environmental stimuli or allergen (C) infiltrate in lung tumor and express cytotoxic molecules and effector cytokines.