TIPE polarity proteins are required for mucosal deployment of T lymphocytes and mucosal defense against bacterial infection

Mingyue Li,Zienab Etwebi,Youhai H Chen,Honghong Sun,Jiyeon Yu,Mayassa J Bou-Dargham

doi:10.1186/s43556-021-00059-8

Mingyue Li, Zienab Etwebi + Show 4 more

Open Access

https://doi.org/10.1186/s43556-021-00059-8

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Abstract

Mucosal surfaces are continuously exposed to, and challenged by, numerous commensal and pathogenic organisms. To guard against infections, a majority of the thymus-derived T lymphocytes are deployed at the mucosa. Although chemokines are known to be involved in the mucosal lymphocyte deployment, it is not clear whether lymphocytes enter the mucosa through directed migration or enhanced random migration. Here we report that TIPE (tumor necrosis factor-α-induced protein 8 (TNFAIP8)-like) proteins mediate directed migration of T lymphocytes into lung mucosa, and they are crucial for mucosal immune defense against Streptococcus pneumoniae infection. Knockout of both Tnfaip8 and Tipe2, which encode polarity proteins that control the directionality of lymphocyte migration, significantly reduced the numbers of T lymphocytes in the lung of mice. Compared with wild-type mice, Tnfaip8−/−Tipe2−/− mice also developed more severe infection with more pathogens entering blood circulation upon nasal Streptococcus pneumoniae challenge. Single-cell RNA-sequencing analysis revealed that TIPE proteins selectively affected mucosal homing of a unique subpopulation of T cells, called “T cells-2”, which expressed high levels of Ccr9, Tcf7, and Rag1/2 genes. TNFAIP8 and TIPE2 appeared to have overlapping functions since deficiency in both yielded the strongest phenotype. These data demonstrate that TIPE family of proteins are crucial for lung mucosal immunity. Strategies targeting TIPE proteins may help develop mucosal vaccines or treat inflammatory diseases of the lung.

Highlights

Mucosal surfaces are the first line of immune defense against luminal pathogens [1]
These results demonstrate that tumor necrosis factor-α-induced protein 8-like (TIPE) proteins are regulators of T lymphocyte positioning in lung mucosa and are important for protection against bacterial infection
Chemokine Receptor 9 (CCR9) plays an essential role in recruiting intraepithelial lymphocytes (IELs) to the small intestine [30, 31], and engages in early mucosal T cell development [12]

Summary

Introduction

Mucosal surfaces are the first line of immune defense against luminal pathogens [1]. The respiratory and digestive organs have two of the largest mucosal surfaces in the body [2, 3]. Previous evidence showed that C-C Motif Chemokine Receptor 9 (CCR9), a gut-homing receptor expressed in IELs, is crucial for lymphocyte trafficking It acts as the receptor for C-C Motif Chemokine Ligand 25 (CCL25) [12]. Streptococcus pneumoniae (Sp) is the leading cause of bacterial pneumonia, especially in elderly people, young children, and immune-deficient patients [13] It is a gram-positive bacterium that is commonly found on mucosal surfaces [14]. Our previous research demonstrated the role of TIPE2 and TNFAIP8 in systematic Listeria monocytogenes (L. monocytogenes) infection induced by intravenous administration of bacteria. We report here that TIPE proteins (TNFAIP8 and TIPE2) protect mice at mucosal sites from local Streptococcus pneumoniae infection by regulating lymphocyte homing, as directed by CCR9

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Materials and methods