Sustained T cell Rap1 signaling is protective in the collagen-induced arthritis model of rheumatoid arthritis.
OBJECTIVE
Defective activation of T cell receptor-proximal signaling proteins, such as the small GTPase Rap1, is thought to contribute to the pathologic behavior of rheumatoid arthritis (RA) synovial T cells. This study was undertaken to determine whether maintaining Rap1 signaling in murine T cells modifies disease onset or severity in collagen-induced arthritis (CIA).


METHODS
CIA experiments were conducted using wild-type and RapV12-transgenic mice, which express an active mutant of Rap1 in the T cell compartment. Mice were assessed using macroscopic, microscopic, and radiologic measures, and serum levels of anticollagen antibodies were measured by enzyme-linked immunosorbent assay. Phenotypic and functional characterization of wild-type and RapV12-transgenic T cells under homeostatic conditions and during disease onset was performed by flow cytometry.


RESULTS
Disease incidence and severity, synovial infiltration, joint destruction, and anticollagen antibody production were significantly reduced in RapV12-transgenic mice. Although the numbers and percentages of CD3+, CD4+, and CD8+ (naive, effector, and memory) T cells, Treg cells, and Th17 cells were equivalent in wild-type and RapV12-transgenic mice, a significant decrease in the percentage of tumor necrosis factor α-secreting CD8+ T cells was observed in RapV12-transgenic mice during CIA. RapV12-transgenic T cells also inefficiently expressed inducible costimulator and CD40L costimulatory proteins involved in B cell immunoglobulin class switching.


CONCLUSIONS
Our findings indicate that maintenance of T cell Rap1 signaling in murine T cells reduces disease incidence and severity in CIA, which are associated with specific defects in T cell effector function. Therefore, the restoration of Rap1 function in RA synovial T cells may have therapeutic benefit in RA.
Abreu
Joana R F
JR
Academic Medical Center and University of Amsterdam, Amsterdam, The Netherlands.
Krausz
Sarah
S
Dontje
Wendy
W
Grabiec
Aleksander M
AM
de Launay
Daphne
D
Nolte
Martijn A
MA
Tak
Paul P
PP
Reedquist
Kris A
KA
D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology / Q000378:metabolism*; D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000276:immunology; D013583:Synovial Membrane / Q000276:immunology / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D020827:rap1 GTP-Binding Proteins / Q000276:immunology / Q000378:metabolism*
D020827:rap1 GTP-Binding Proteins