Tissue-resident memory CD8 ⁺ T cells cooperate with CD4 ⁺ T cells to drive compartmentalized immunopathology in the CNS

Abstract

In chronic inflammatory diseases of the central nervous system (CNS), immune cells persisting behind the blood-brain barrier are supposed to promulgate local tissue destruction. The drivers of such compartmentalized inflammation remain unclear, but tissue-resident memory T cells (T RM ) represent a potentially important cellular player in this process. Here, we investigated whether resting CD8 + T RM persisting after cleared infection with attenuated lymphocytic choriomeningitis virus (LCMV) can initiate immune responses directed against cognate self-antigen in the CNS. We demonstrated that time-delayed conditional expression of the LCMV glycoprotein as neo-self-antigen by glia cells reactivated CD8 + T RM . Subsequently, CD8 + T RM expanded and initiated CNS inflammation and immunopathology in an organ-autonomous manner independently of circulating CD8 + T cells. However, in the absence of CD4 + T cells, TCF-1 + CD8 + T RM failed to expand and differentiate into terminal effectors. Similarly, in human demyelinating CNS autoimmune lesions, we found CD8 + T cells expressing TCF-1 that predominantly exhibited a T RM -like phenotype. Together, our study provides evidence for CD8 + T RM -driven CNS immunopathology and sheds light on why inflammatory processes may evade current immunomodulatory treatments in chronic autoimmune CNS conditions.

Tissue-resident CD8 + T cells drive compartmentalized and chronic autoimmune damage against CNS neurons

“…Our study, together with the companion article (45), demonstrates the important contribution of tissue-resident CD8 + T cells to the chronicity of destructive CNS autoimmune experimental disease. Moreover, CD8 + T cells harboring a T RM -like phenotype and expressing key functional molecules uncovered in the mouse models were prevalent within brain tissues of patients suffering from neuron-targeting autoimmune diseases.…”

Persistent virus-specific and clonally expanded antibody secreting cells respond to induced self antigen in the CNS

“…tamoxifen (TAM) administration induces full-length LCMV-GP as a neo-self antigen in astrocytes and results in bTRM reactivation and development of locomotor deficits (Vincenti et al 2022). Littermate Stop-GP flox/+ mice, termed STOP:GP, served as post-infection controls as they lack the GFAP-Cre ERT2tg/+ and therefore do not express the full-length LCMV GP upon TAM administration (Vincenti et al 2022) (Figure 1A). To exclude recruitment of peripheral B cells during induced neo-self antigen expression (LCMV-GP), we included an experimental condition that received i.p.…”

“…Six weeks after viral clearance, intraperitoneal (i.p.) tamoxifen (TAM) administration induces full-length LCMV-GP as a neo-self antigen in astrocytes and results in bTRM reactivation and development of locomotor deficits (Vincenti et al 2022). Littermate Stop-GP flox/+ mice, termed STOP:GP, served as post-infection controls as they lack the GFAP-Cre ERT2tg/+ and therefore do not express the full-length LCMV GP upon TAM administration (Vincenti et al 2022) (Figure 1A).…”

“…The C57Bl/6J GFAP:GP (GFAP-Cre ERT2 tg/+ ;Stop-GP flox/+ ) mouse line was bred by crossing C57Bl/6 GFAP-CreERT2 mice (Hirrlinger et. al 2006) expressing the TAM-inducible Cre-recombinase under the astrocyte-specific GFAP promoter with C57Bl/6J Stop-GP mice (Vincenti et al 2022). The C57BL/ 6J MOG:GP (MOGi Cre/+ : Stop-GP flox/+ ) mouse line was generated as described previously (Page et al 2021).…”

“…Thereby, T cells have previously been shown to be able to locally reside in a variety of non-lymphoid tissues, including the CNS, and to adopt a tissue-resident memory phenotype (Trm)(Jiang et al 2012; Schenkel and Masopust 2014; Carbone 2015; Clark 2015; Dijkgraaf et al 2019). Such Trm are poised to respond to secondary exposures (Steinbach et al 2016; Urban et al 2020; Vincenti et al 2022) or can participate in compartmentalized inflammation in the CNS (Vincenti et al 2022), In contrast, much less is known about the phenotype and function of tissue-resident B cells (Allie and Randall 2020; Gray and Farber 2022) and their interference with circulating counterparts. This is particularly true in the case of the CNS, where the formation and existence of resident B cells is still under debate.…”