The mechanisms whereby autoreactive T cells escape peripheral tolerance establishing thus autoimmune diseases in humans remain an unresolved question. Here, we demonstrate that autoreactive polyfunctional CD8(+) T cells recognizing self-antigens (i.e., vimentin, actin cytoplasmic 1, or non-muscle myosin heavy chain 9 epitopes) with high avidity, counter-regulate Tregs by killing them, in a consistent percentage of rheumatoid arthritis (RA) patients. Indeed, these CD8(+) T cells express a phenotype and gene profile of effector (eff) cells and, upon antigen-specific activation, kill Tregs indirectly in an NKG2D-dependent bystander fashion in vitro. This data provides a mechanistic basis for the finding showing that AE-specific (CD107a(+)) CD8(+) T killer cells correlate, directly with the disease activity score, and inversely with the percentage of activated Tregs, in both steady state and follow-up studies in vivo. In addition, multiplex immunofluorescence imaging analyses of inflamed synovial tissues in vivo show that a remarkable number of CD8(+) T cells express granzyme-B and selectively contact FOXP3(+) Tregs, some of which are in an apoptotic state, validating hence the possibility that CD8(+) Teff cells can counteract neighboring Tregs within inflamed tissues, by killing them. Alternatively, the disease activity score of a different subset of patients is correlated with the expansion of a peculiar subpopulation of autoreactive low avidity, partially-activated (pa)CD8(+) T cells that, despite they conserve the conventional naive (N) phenotype, produce high levels of tumor necrosis factor (TNF)-alpha and exhibit a gene expression signature of a progressive activation state. Tregs directly correlate with the expansion of this autoreactive (low avidity) paCD8(+) TN cell subset in vivo, and efficiently control their differentiation rather their proliferation in vitro. Interestingly, auto-reactive high avidity CD8(+) Teff cells or low avidity paCD8(+) TN cells are significantly expanded in RA patients who would become non-responders or patients who would become responders to TNF-alpha inhibitor therapy, respectively. These data provide evidence of a previously undescribed role of such mechanisms in the progression and therapy of RA.

Cammarata, I., Martire, C., Citro, A., Raimondo, D., Fruci, D., Melaiu, O., et al. (2019). Counter-regulation of regulatory T cells by autoreactive CD8 + T cells in rheumatoid arthritis. JOURNAL OF AUTOIMMUNITY, 99, 81-97 [10.1016/j.jaut.2019.02.001].

Counter-regulation of regulatory T cells by autoreactive CD8 + T cells in rheumatoid arthritis

Melaiu O.;
2019

Abstract

The mechanisms whereby autoreactive T cells escape peripheral tolerance establishing thus autoimmune diseases in humans remain an unresolved question. Here, we demonstrate that autoreactive polyfunctional CD8(+) T cells recognizing self-antigens (i.e., vimentin, actin cytoplasmic 1, or non-muscle myosin heavy chain 9 epitopes) with high avidity, counter-regulate Tregs by killing them, in a consistent percentage of rheumatoid arthritis (RA) patients. Indeed, these CD8(+) T cells express a phenotype and gene profile of effector (eff) cells and, upon antigen-specific activation, kill Tregs indirectly in an NKG2D-dependent bystander fashion in vitro. This data provides a mechanistic basis for the finding showing that AE-specific (CD107a(+)) CD8(+) T killer cells correlate, directly with the disease activity score, and inversely with the percentage of activated Tregs, in both steady state and follow-up studies in vivo. In addition, multiplex immunofluorescence imaging analyses of inflamed synovial tissues in vivo show that a remarkable number of CD8(+) T cells express granzyme-B and selectively contact FOXP3(+) Tregs, some of which are in an apoptotic state, validating hence the possibility that CD8(+) Teff cells can counteract neighboring Tregs within inflamed tissues, by killing them. Alternatively, the disease activity score of a different subset of patients is correlated with the expansion of a peculiar subpopulation of autoreactive low avidity, partially-activated (pa)CD8(+) T cells that, despite they conserve the conventional naive (N) phenotype, produce high levels of tumor necrosis factor (TNF)-alpha and exhibit a gene expression signature of a progressive activation state. Tregs directly correlate with the expansion of this autoreactive (low avidity) paCD8(+) TN cell subset in vivo, and efficiently control their differentiation rather their proliferation in vitro. Interestingly, auto-reactive high avidity CD8(+) Teff cells or low avidity paCD8(+) TN cells are significantly expanded in RA patients who would become non-responders or patients who would become responders to TNF-alpha inhibitor therapy, respectively. These data provide evidence of a previously undescribed role of such mechanisms in the progression and therapy of RA.
Pubblicato
Rilevanza internazionale
Articolo
Esperti anonimi
Settore MED/05
English
Rheumatoid arthritis
Autoreactive CD8(+) T cells
Regulatory T cells
Counter-regulation
Cammarata, I., Martire, C., Citro, A., Raimondo, D., Fruci, D., Melaiu, O., et al. (2019). Counter-regulation of regulatory T cells by autoreactive CD8 + T cells in rheumatoid arthritis. JOURNAL OF AUTOIMMUNITY, 99, 81-97 [10.1016/j.jaut.2019.02.001].
Cammarata, I; Martire, C; Citro, A; Raimondo, D; Fruci, D; Melaiu, O; D'Oria, V; Carone, C; Peruzzi, G; Cerboni, C; Santoni, A; Sidney, J; Sette, A; Paroli, M; Caccavale, R; Milanetti, E; Riminucci, M; Timperi, E; Piconese, S; Manzo, A; Montecucco, C; Scrivo, R; Valesini, G; Cariani, E; Barnaba, V
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2108/305959
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