Balancing Inflammation and Central Nervous System Homeostasis: T Cell Receptor Signaling in Antiviral Brain TRM Formation and Function.

Colleen S Netherby-Winslow,Aron E Lukacher,Katelyn N Ayers

doi:10.3389/fimmu.2020.624144

Abstract

Tissue-resident memory (TRM) CD8 T cells provide early frontline defense against regional pathogen reencounter. CD8 TRM are predominantly parked in nonlymphoid tissues and do not circulate. In addition to this anatomic difference, TRM are transcriptionally and phenotypically distinct from central-memory T cells (TCM) and effector-memory T cells (TEM). Moreover, TRM differ phenotypically, functionally, and transcriptionally across barrier tissues (e.g., gastrointestinal tract, respiratory tract, urogenital tract, and skin) and in non-barrier organs (e.g., brain, liver, kidney). In the brain, TRM are governed by a contextual milieu that balances TRM activation and preservation of essential post-mitotic neurons. Factors contributing to the development and maintenance of brain TRM, of which T cell receptor (TCR) signal strength and duration is a central determinant, vary depending on the infectious agent and modulation of TCR signaling by inhibitory markers that quell potentially pathogenic inflammation. This review will explore our current understanding of the context-dependent factors that drive the acquisition of brain (b)TRM phenotype and function, and discuss the contribution of TRM to promoting protective immune responses in situ while maintaining tissue homeostasis.

Highlights

Development of long-lived T cell memory is vital to protection against microbial pathogens and cancer, and a goal of vaccination efforts
Because virus-specific CD8 TEFF express high-affinity T cell receptor (TCR), we suggested that these cells were the progeny of high-affinity effectors recruited to the brain during the acute stage of infection [68]
Because antigen is required for CD8 brain tissue-resident memory CD8 T cell (bTRM) formation but not programmed cell death protein-1 (PD-1) maintenance, it is possible that PD-1 is an important regulator of Tissue-resident memory (TRM) function in the brain microenvironment

Summary

Introduction

Development of long-lived T cell memory is vital to protection against microbial pathogens and cancer, and a goal of vaccination efforts. It is likely that brain-specific factors contribute to formation of TRM and their functional attributes due to the exquisite need to balance immune activation and tissue preservation in the CNS. Regulating TCR signaling via inhibitory receptors, such as programmed cell death protein-1 [PD-1(CD279)], may be essential for TRM maintenance in particular tissues by operating as a rheostat to fine tune T cell activation and effector function.

Results

Conclusion