Activated CD8 + lymphocytes infiltrate the brain in response to many viral infections; where some remain stationed long term as memory T cells. Brain-resident memory T cells (bT RM ) are positioned to impart immediate defense against recurrent or reactivated infection. The cytokine and chemokine milieu present within a tissue is critical for T RM generation and retention; and reciprocal interactions exist between brain-resident glia and bT RM . High concentrations of TGF-β are found within brain and this cytokine has been shown to induce CD103 (integrin αeβ7) expression. The majority of T cells persisting within brain express CD103, which aids in retention through interaction with E-cadherin. Likewise, cytokines produced by T cells also modulate microglia. The anti-inflammatory cytokine IL-4 has been shown to preferentially polarize microglial cells toward an M2 phenotype, with a corresponding increase in E-cadherin expression. These findings demonstrate that the brain microenvironment, both during and following inflammation, prominently contributes to the role of CD103 in T cell persistence. Further evidence shows that microglia, and astrocytes, upregulate programmed death (PD) ligand 1 during neuroinflammation, likely to limit neuropathology, and the PD-1: PD-L1 pathway also aids in bT RM generation and retention. Upon reactivation of quiescent neurotropic viruses, bT RM may respond to small amounts of de novo-produced viral antigen by rapidly releasing IFN-γ, resulting in interferon-stimulated gene expression in surrounding glia, thereby amplifying activation of a small number of adaptive immune cells into an organ-wide innate antiviral response. While advantageous from an antiviral perspective; over time, recall response-driven, organ-wide innate immune activation likely has cumulative neurotoxic and neurocognitive consequences.
Bibliographical noteFunding Information:
This project was supported by award numbers NS-038836 from the National Institute of Neurological Disorders and Stroke and MH-066703 from the National Institute of Mental Health.
© 2019, Mary Ann Liebert, Inc., publishers.
- resident memory T cells
- viral infection