TY - JOUR
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
PY - 2019/1/1
Y1 - 2019/1/1
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.
AB -
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.
KW - Autoreactive CD8 T cells
KW - Counter-regulation
KW - Regulatory T cells
KW - Rheumatoid arthritis
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U2 - 10.1016/j.jaut.2019.02.001
DO - 10.1016/j.jaut.2019.02.001
M3 - Article
AN - SCOPUS:85061609086
JO - Journal of Autoimmunity
JF - Journal of Autoimmunity
SN - 0896-8411
ER -