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Complement regulatory protein Crry/p65 costimulation expands natural Treg cells with enhanced suppressive properties in proteoglycan-induced arthritis

AuthorsOjeda, Gloria; Pini, Eliana; Eguiluz, César; Montes-Casado, María; Broere, Femke; van Eden, Willem.; Rojo, José María CSIC ORCID ; Portolés, Pilar
Issue DateJun-2011
CitationArthritis & Rheumatism 63(3):1562-1572(2011)
AbstractObjective To investigate the costimulatory role of Crry/p65 (Crry), a membrane complement regulatory protein, on the expansion and function of natural Treg cells and their ability to ameliorate proteoglycan-induced arthritis (PGIA), an animal model of inflammatory arthritis in which the role of natural Treg cells is not well established. Methods CD4+CD25+ natural Treg cells from BALB/c mice were activated in vitro and costimulated by Crry. The expanded cells were phenotypically characterized, and their suppressive effect on T cell proliferation was assayed in vitro. The potential prophylactic and therapeutic effects of this population versus those of natural Treg cells in PGIA were studied. The clinical score, histology, the antigen-specific isotype antibody pattern, in vitro T cell responses, and the presence of Treg cells in the paws were studied. Results Crry costimulation enhanced the in vitro expansion of natural Treg cells while maintaining their phenotypic and suppressive properties. Crry-expanded Treg cells had stronger suppressive properties in vivo and a longer ameliorating effect in the PGIA model than did natural Treg cells. Crry-expanded Treg cells suppressed T cell– and B cell–dependent responses in PGIA, changing the pathogenic antibody isotype pattern and decreasing antigen-dependent secretion of cytokines, including interferon-γ, interleukin-12 (IL-12), and IL-17. Increased FoxP3 expression was detected in the paws of mice transferred with Crry-expanded Treg cells. Conclusion Crry-mediated costimulation facilitates in vitro expansion of natural Treg cells while maintaining their suppressive properties in vitro and in vivo in the PGIA model. These results highlight the potential of the complement regulatory protein Crry to costimulate and expand natural Treg cells capable of suppressing disease in an animal model of chronic inflammatory arthritis. Thymus-derived CD4+CD25+FoxP3+ natural Treg cells are important for self-tolerance and prevention of autoimmunity (1, 2). However, the therapeutic application of Treg cells poses important problems, including the absence of specific, exclusive surface markers allowing their isolation by standard methods; the low number of Treg cells in the lymphoid organs or blood of healthy individuals; the lack of definitive data concerning the growth factors and stimuli specifically controlling expansion of Treg cells; and their own anergic nature, proliferating with difficulty in response to antigenic stimuli in vitro. In vitro, Treg cell–mediated suppression requires a signal through the T cell receptor, but once activated, suppression is nonspecific. Attempts have been made to expand natural Treg cells in vitro, using different stimuli and costimuli, without abrogating their suppressive activity (3–5).
Description11 páginas, 6 figuras -- PAGS nros. 1562-1572
Publisher version (URL)https://dx.doi.org/10.1002/art.30328
Appears in Collections:(CIB) Artículos
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