Counter-regulation of regulatory T cells by autoreactive CD8+ T cells in rheumatoid arthritis. (May 2019)

• Record Type: Journal Article
• Authors: 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
• Is Part Of: Journal of autoimmunity. Volume 99(2019)
• Page Start: 81
• Page End: 97
• Publication Date: 2019-05
• Subjects: Rheumatoid arthritis -- Autoreactive CD8+ T cells -- Regulatory T cells -- Counter-regulation; TCRs T cell receptors -- Treg regulatory T cell -- N naïve -- eff effector -- VIME vimentin -- ACTB actin cytoplasmic 1 -- MYH9 non-muscle myosin heavy chain 9 -- AE apoptotic epitope -- HDs healthy donors -- DCs dendritic cells -- L ligand -- RA rheumatoid arthritis -- TNF tumor necrosis factor -- NRs non-responders -- Rs responders -- ACR American College of Rheumatology -- DMARDs disease-modifying anti-rheumatic drugs -- DAS28 Disease Activity Score 28 joints -- EULAR European League Against Rheumatism -- R receptor -- SF synovial fluid -- MFI mean fluorescence intensity -- IHC immunohistochemical -- IF immunofluorescence -- CMV cytomegalovirus -- FITC fluorescein isothiocyanate -- PI propidium iodide -- EM effector memory -- EMRA effector memory RA+ -- APC allophycocyanin -- FSC-A forward scatter area -- SSC-A side scatter area -- CTLA-4 Cytotoxic T-Lymphocyte Antigen-4 -- PD-1 programmed death-1 -- IFN interferon -- p phosphorylated -- GZM granzyme -- CFSE carboxyfluorescein succinimidyl ester -- FC flow cytometry -- NKG2D NK group 2 member D -- MTE Multiplexed Target Enrichment -- N-HDs naïve in healthy donors -- N-Ps naïve in patients -- Eff-HDs effector cells in healthy donors -- Eff-Ps effector cells in patients -- CDF cumulative distribution function -- PCA principal component analysis -- RF rheumatoid factor -- ACPA anti-citrullinated protein antibody -- CRP C reactive protein -- ESR erythrocyte sedimentation rate -- Eomes Eomesodermin -- T-bet transcription factor T-box -- CB cord blood -- pa partially activated -- TMNP memory T cells with a naive phenotype -- act activated; Autoimmunity -- Periodicals; Autoimmune diseases -- Periodicals; Autoantibodies -- Periodicals; Autoimmune Diseases -- Periodicals; Auto-immunité -- Périodiques; Maladies auto-immunes -- Périodiques; Electronic journals; 616.978005
• DOI: 10.1016/j.jaut.2019.02.001
• Languages: English
• ISSNs: 0896-8411

Abstract

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. Highlights: Autoreactive CD8 + TN or eff cells differently affect Tregs to their vantage in RA. Autoreactive low avidity CD8 + TN cells producing TNF-α are sustained by Tregs. Autoreactive high avidity CD8 + Teff cells resist Tregs by killing them. These distinctive mechanisms condition the response to anti-TNF therapy. They could contribute for designing innovative therapeutic strategies.