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

Ilenia Cammarata, Carmela Martire, Alessandra Citro, Domenico Raimondo, Doriana Fruci, Ombretta Melaiu, Valentina D'Oria, Chiara Carone, Giovanna Peruzzi, Cristina Cerboni, Angela Santoni, John Sidney, Alessandro Sette, Marino Paroli, Rosalba Caccavale, Edoardo Milanetti, Mara Riminucci, Eleonora Timperi, Silvia Piconese, Antonio ManzoCarlomaurizio Montecucco, Rossana Scrivo, Guido Valesini, Elisabetta Cariani, Vincenzo Barnaba

Research output: Contribution to journalArticle

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 naïve (N) phenotype, produce high levels of tumor necrosis factor (TNF)-α 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, autoreactive 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-α inhibitor therapy, respectively. These data provide evidence of a previously undescribed role of such mechanisms in the progression and therapy of RA.

Original languageEnglish
Pages (from-to)81-97
Number of pages17
JournalJournal of Autoimmunity
Volume99
DOIs
Publication statusPublished - May 2019

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Regulatory T-Lymphocytes
Rheumatoid Arthritis
T-Lymphocytes
Eragrostis
Tumor Necrosis Factor-alpha
Peripheral Tolerance
Phenotype
Granzymes
Myosin Heavy Chains
Autoantigens
Vimentin
Transcriptome
Autoimmune Diseases
Fluorescent Antibody Technique
Actins
Epitopes
Antigens
Therapeutics
Genes

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Counter-regulation of regulatory T cells by autoreactive CD8+ T cells in rheumatoid arthritis. / Cammarata, Ilenia; Martire, Carmela; Citro, Alessandra; Raimondo, Domenico; Fruci, Doriana; Melaiu, Ombretta; D'Oria, Valentina; Carone, Chiara; Peruzzi, Giovanna; Cerboni, Cristina; Santoni, Angela; Sidney, John; Sette, Alessandro; Paroli, Marino; Caccavale, Rosalba; Milanetti, Edoardo; Riminucci, Mara; Timperi, Eleonora; Piconese, Silvia; Manzo, Antonio; Montecucco, Carlomaurizio; Scrivo, Rossana; Valesini, Guido; Cariani, Elisabetta; Barnaba, Vincenzo.

In: Journal of Autoimmunity, Vol. 99, 05.2019, p. 81-97.

Research output: Contribution to journalArticle

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 2019, 'Counter-regulation of regulatory T cells by autoreactive CD8+ T cells in rheumatoid arthritis', Journal of Autoimmunity, vol. 99, pp. 81-97. https://doi.org/10.1016/j.jaut.2019.02.001
Cammarata, Ilenia ; Martire, Carmela ; Citro, Alessandra ; Raimondo, Domenico ; Fruci, Doriana ; Melaiu, Ombretta ; D'Oria, Valentina ; Carone, Chiara ; Peruzzi, Giovanna ; Cerboni, Cristina ; Santoni, Angela ; Sidney, John ; Sette, Alessandro ; Paroli, Marino ; Caccavale, Rosalba ; Milanetti, Edoardo ; Riminucci, Mara ; Timperi, Eleonora ; Piconese, Silvia ; Manzo, Antonio ; Montecucco, Carlomaurizio ; Scrivo, Rossana ; Valesini, Guido ; Cariani, Elisabetta ; Barnaba, Vincenzo. / Counter-regulation of regulatory T cells by autoreactive CD8+ T cells in rheumatoid arthritis. In: Journal of Autoimmunity. 2019 ; Vol. 99. pp. 81-97.
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T1 - Counter-regulation of regulatory T cells by autoreactive CD8+ T cells in rheumatoid arthritis

AU - Cammarata, Ilenia

AU - Martire, Carmela

AU - Citro, Alessandra

AU - Raimondo, Domenico

AU - Fruci, Doriana

AU - Melaiu, Ombretta

AU - D'Oria, Valentina

AU - Carone, Chiara

AU - Peruzzi, Giovanna

AU - Cerboni, Cristina

AU - Santoni, Angela

AU - Sidney, John

AU - Sette, Alessandro

AU - Paroli, Marino

AU - Caccavale, Rosalba

AU - Milanetti, Edoardo

AU - Riminucci, Mara

AU - Timperi, Eleonora

AU - Piconese, Silvia

AU - Manzo, Antonio

AU - Montecucco, Carlomaurizio

AU - Scrivo, Rossana

AU - Valesini, Guido

AU - Cariani, Elisabetta

AU - Barnaba, Vincenzo

N1 - Copyright © 2019 Elsevier Ltd. All rights reserved.

PY - 2019/5

Y1 - 2019/5

N2 - 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 naïve (N) phenotype, produce high levels of tumor necrosis factor (TNF)-α 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, autoreactive 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-α inhibitor therapy, respectively. These data provide evidence of a previously undescribed role of such mechanisms in the progression and therapy of RA.

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