Increased autophagy in CD4+T cells of rheumatoid arthritis patients results in T-cell hyperactivation and apoptosis resistance.
Rheumatoid arthritis (RA) is an autoimmune disease hallmarked by aberrant cellular homeostasis, resulting in hyperactive CD4+T cells that are more resistant to apoptosis. Both hyperactivation and resistance to apoptosis may contribute to the pathogenicity of CD4+T cells in the autoimmune process. A better knowledge of the mechanisms determining such impaired homeostasis could contribute significantly to both the understanding and the treatment of the disease. Here we investigated whether autophagy, is dysregulated in CD4+T cells of RA patients, resulting in disturbed T-cell homeostasis. We demonstrate that the rate of autophagy is significantly increased in CD4+T cells from RA patients, and that increased autophagy is also a feature of in vitro activated CD4+T cells. The increased apoptosis resistance observed in CD4+T cells from RA patients was significantly reversed upon autophagy inhibition. These mechanisms may contribute to RA pathogenesis, as autophagy inhibition reduced both arthritis incidence and disease severity in a mouse collagen induced arthritis mouse model. Conversely, in Atg5flox/flox-CD4-Cre+mice, in which all T cells are autophagy deficient, T cells showed impaired activation and proliferation. These data provide novel insight into the pathogenesis of RA and underscore the relevance of autophagy as a promising therapeutic target.
Translational Research Laboratory, Inflammatory and Infectious Disease Center, Sanford-Burnham Medical Research Institute, La Jolla, USA.|Eureka Institute for Translational Medicine, Siracusa, Italy.|Division of Pediatrics, University Medical Center, Utrecht, The Netherlands.|Center for Molecular Medicine, University Medical Center, Utrecht, The Netherlands.
Jorg
J
van Loosdregt
Translational Research Laboratory, Inflammatory and Infectious Disease Center, Sanford-Burnham Medical Research Institute, La Jolla, USA.|SingHealth Translational Immunology and Inflammation Centre, Duke-NUS Graduate Medical School, Singapore, Singapore.|Eureka Institute for Translational Medicine, Siracusa, Italy.
Maura
M
Rossetti
Translational Research Laboratory, Inflammatory and Infectious Disease Center, Sanford-Burnham Medical Research Institute, La Jolla, USA.|SingHealth Translational Immunology and Inflammation Centre, Duke-NUS Graduate Medical School, Singapore, Singapore.
Roberto
R
Spreafico
Translational Research Laboratory, Inflammatory and Infectious Disease Center, Sanford-Burnham Medical Research Institute, La Jolla, USA.
Maryam
M
Moshref
Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, USA.
Merissa
M
Olmer
Division of Rheumatology, Scripps Clinic, San Diego, USA.
Gary W
GW
Williams
SingHealth Translational Immunology and Inflammation Centre, Duke-NUS Graduate Medical School, Singapore, Singapore.
Pavanish
P
Kumar
Division of Rheumatology, Scripps Clinic, San Diego, USA.
Dana
D
Copeland
Division of Rheumatology, Scripps Clinic, San Diego, USA.
Ken
K
Pischel
Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, USA.
Martin
M
Lotz
Translational Research Laboratory, Inflammatory and Infectious Disease Center, Sanford-Burnham Medical Research Institute, La Jolla, USA.|SingHealth Translational Immunology and Inflammation Centre, Duke-NUS Graduate Medical School, Singapore, Singapore.|Eureka Institute for Translational Medicine, Siracusa, Italy.
Salvatore
S
Albani
D000368:Aged; D000818:Animals; D017209:Apoptosis; D001172:Arthritis, Rheumatoid / Q000276:immunology*; D001343:Autophagy / Q000235:genetics*; D000071187:Autophagy-Related Protein 5 / Q000235:genetics / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D024043:Collagen Type II / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008213:Lymphocyte Activation / Q000235:genetics; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D008875:Middle Aged
C495773:Atg5 protein, mouse; D000071187:Autophagy-Related Protein 5; D024043:Collagen Type II
Activation; Apoptosis resistance; Autophagy; Rheumatoid arthritis; T cells