Guarding the perimeter: protection of the mucosa by tissue-resident memory T cells

Abstract

Mucosal tissues are continually bombarded with infectious agents seeking to gain entry into the body. The absence of a tough physical exterior layer surrounding these tissues creates a unique challenge for the immune system, which manages to provide broad protection against a plethora of different organisms with the aid of special adaptations that augment immunity at these vulnerable sites. For example, specialized populations of memory T lymphocytes reside at initial sites of pathogen entry into the body, where they provide an important protective barrier. Similar anatomically-confined populations of pathogen-specific CD8 T cells can be found near the outer margins of the body following recovery from a variety of local infections, where they share very similar phenotypic characteristics. How these tissue-resident T cells are retained in a single anatomic location where they can promote immunity is beginning to be defined. Here, we will review current knowledge of the mechanisms that help establish and maintain these regional lymphocytes in the mucosal tissues and discuss relevant data that enhance our understanding of the contribution of these lymphocyte populations to protective immunity against infectious diseases.

Figure 1

Anatomic and cellular features of the intestinal mucosal immune system. Priming by specialized dendritic cells (DCs) in the immune-inductive sites of the intestine, the Peyer’s patch, and the mesenteric lymph node (MLN) results in the induction of intestine-specific homing molecules, α4β7 and CCR9, which allows activated T cells to enter the effector sites, the lamina propria (LP) and the epithelium. Local effects of tumor growth factor-β (TGFβ) induce αEβ7 expression (CD103=αE), and CD69 is induced by unknown factors. CD103 promotes T-cell retention in the epithelium, and CD69 may have similar effects by downmodulating the activity of sphingosine-1-phosphate receptor 1 (S1P1). Retention of regional or resident memory T cells (Trms) enhances protection to reinfection. IEL, intraepithelial lymphocyte.

Figure 2

Parameters affecting the CD8 T-cell response to influenza virus infection. Influenza virus infections begin in the large airways and descend to the alveoli. Hemagglutinin binds to sialic acid residues on the surface of the epithelial cells, which become infected and produce new virus. Neuraminidase helps the new virus escape from the host cells by removing host sialic acid. Mucus-producing and ciliated cells slow the infection by expelling particulate matter from the lung airways. Neuraminidase and the αVβ8 integrin can activate tumor growth factor-β (TGFβ), which promotes αEβ7 integrin (CD103) expression on local pathogen-specific cytotoxic T lymphocytes, which promotes retention in the airways through interactions with E-cadherin.

Figure 3

Effector CD8 T-cell localization in the lung after influenza virus infection. C57BL/6 mice received 1 × 10³ nucleoprotein (NP)-specific green fluorescent protein (GFP)+ F5 T-cell receptor (TCR) transgenic CD8 T cells followed by infection with E61-13-H17 influenza virus. After 10 days, the lung was imaged using confocal microscopy. Epithelial cells were identified by anti-Epcam staining (red) and blood vessels revealed by anti-CD31 staining (blue). GFP+ F5 cells are shown in green. Image was acquired at original magnification × 20.