Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor

PD-1, a 55 kDa transmembrane protein containing an immunoreceptor tyrosine- based inhibitory motif, is induced in lymphocytes and monocytic cells follo wing activation. Aged C57BL/6(B6)-PD-1(-/-) congenic mice spontaneously dev eloped characteristic lupus-like proliferative arthritis and glomerulonephr itis with predominant IgG3 deposition, which were markedly accelerated by i ntroduction of a Fas mutation (lpr). Introduction of a PD-1 null mutation i nto the 2C-TCR (anti-H-2L(d)) transgenic mice of the H-2(b/d) background re sulted in the chronic and systemic graft-versus-host-like disease. Furtherm ore, CD8(+)2C-TCR+PD-1(-/-) cells exhibited markedly augmented proliferatio n in vitro in response to H-2(d) allogenic cells. Collectively, it is sugge sted that PD-1 is involved in the maintenance of peripheral self-tolerance by serving as a negative regulator of immune responses.