B7-H1 Influences the Accumulation of Virus-Specific Tissue Resident Memory T Cells in the Central Nervous System

Abstract

Therapies that target the PD-1/B7-H1 axis have revolutionized cancer treatment, yet precise knowledge of how this pathway provides benefit continues to evolve. Here, we report a novel role for the immune checkpoint ligand B7-H1 in the accumulation of tissue-resident memory CD8+ T-cells (TRM). After intracranial infection, Theiler’s murine encephalomyelitis virus (TMEV) generates TRM that are maintained in the central nervous system (CNS) tissues of B7-H1WT animals. Although no differences in acute T-cell responses between B7-H1WT and B7-H1KO are observed, at long-term periods post-infection the maintenance of CD8+ TRM is diminished in B7-H1KO animals. This is accompanied by redistribution of the resident CD8+ population from primarily CD103+ TRM to a diminished population of TRM and a preponderance of non-specified PD-1+ CD103− CD8+ T-cells. T-cell transfer studies demonstrate that host B7-H1 is necessary for maintaining TRM and limiting accumulation of PD-1+ CD103− CD8+ T-cells. The lack of host B7-H1 results in compromised control of a heterologous virus re-challenge demonstrating a functional defect in TRM mediated virus control. This study reveals a new role for B7-H1 in TRM and pro-inflammatory PD-1+ CD103− CD8+ T-cell accumulation in the CNS and gives insight for using B7-H1/PD-1 blockade in modulating long-term T-cell protection.

Reactive glia promote development of CD103+CD69+ CD8+ T‐cells through programmed cell death‐ligand 1 (PD‐L1)

“…S2). Similar findings have been reported using Theiler's murine encephalomyelitis virus (TMEV), where the authors noted that depletion of PD-L1 resulted in an increased population of CD103 À CD8 þ T-cells that produced IFN-g, which provides additional evidence that IFN-g production by CD103 À CD8 þ T-cells suppressed the accumulation of T RM in PD-L1 KO animals [45].…”

Tissue-resident lymphocytes: from adaptive to innate immunity

“…21,22 Brain T RM cells express CD103 in models of intranasal (i.n.) infection with vesicular stomatitis virus (VSV), 23 intracranial infection with Theiler's murine encephalomyelitis virus (TMEV), 24 and toxoplasma infection, 25 but lack CD103 expression when elicited by LCMV infection. Both CD103 + and CD103 − T RM cells can be found in the kidney.…”

“…For example, lung antigen-specific CD8 + T cells express both the very late antigen-1 (VLA-1) and CD103 after respiratory mucosal immunization 55 ; the tumor necrosis factor (TNF) superfamily molecule LIGHT can promote the generation of lung-resident CD8 + T cells after an acute respiratory virus infection 56 ; and the immune checkpoint ligand B7-H1 is essential for the maintenance and accumulation of virus-specific T RM cells in the central nervous system (CNS): Long-term maintenance of T RM cells is diminished in B7-H1 knockout mice. 24 Transcriptional factors involved in the regulation of T RM differentiation include Hobit, Blimp-1, KLF2, Eomes and Tbet. 15,57,58 In addition, the transcription factor Runx3 was recently identified as a key regulator of T RM cell differentiation that supports the expression of tissue-residency genes and suppresses genes associated with tissue egress and recirculation.…”

“…84 T RM cells are generated and maintained in the CNS tissues after intracranial infection with TMEV, and a lack of this cell population results in compromised control of heterologous virus rechallenge. 24 In addition, T RM cells accumulate within the brain after chronic Toxoplasma gondii infection and contribute to parasite control within the CNS. 25 In the respiratory tract, T RM cells may confer protective immunity against viruses such as RSV, 80,85 Sendai virus, 86 and influenza.…”

Tissue-Specific Control of Tissue-Resident Memory T Cells

“…126 PD-1/PD-L1 interaction is required to limit the accumulation of PD-1 hi CD103 − CD8 + T cells and promote brain T RM population. 129 In contrast to lung and FRT T RM s, the differentiation and maintenance of brain T RM cells are independent of CD4-help. 126,128 Cognate antigen re-challenge activates brain T RM s to recruit circulating memory T cells.…”