Development of Lupus-like Autoimmune Diseases by Disruption of the PD-1 Gene Encoding an ITIM Motif-Carrying Immunoreceptor

Abstract

PD-1, a 55 kDa transmembrane protein containing an immunoreceptor tyrosine-based inhibitory motif, is induced in lymphocytes and monocytic cells following activation. Aged C57BL/6(B6)-PD-1(-/-) congenic mice spontaneously developed characteristic lupus-like proliferative arthritis and glomerulonephritis with predominant IgG3 deposition, which were markedly accelerated by introduction of a Fas mutation (lpr). Introduction of a PD-1 null mutation into the 2C-TCR (anti-H-2Ld) transgenic mice of the H-2(b/d) background resulted in the chronic and systemic graft-versus-host-like disease. Furthermore, CD8+ 2C-TCR+ PD-1(-/-) T cells exhibited markedly augmented proliferation in vitro in response to H-2d allogenic cells. Collectively, it is suggested that PD-1 is involved in the maintenance of peripheral self-tolerance by serving as a negative regulator of immune responses.

Non-myeloablative transplantation of bone marrow expressing self-antigen establishes peripheral tolerance and completely prevents autoimmunity in mice

“…46 The PD-1 pathway has a crucial role in peripheral tolerance induction and maintenance as mice with deletion of PD-1 gene developed systemic autoimmunity. 47 Injection of PD-1 neutralizing monoclonal antibody into disease-resistant mice resulted in the majority (67%) of the mice developing EAE whereas none of the IgG controls developed disease. Although we failed to detect any significant changes in proportion of CD4 þ Foxp3 þ T cells, it remains to be determined whether antigen-specific Tregs were generated in this model.…”

BAFF overexpression and accelerated glomerular disease in mice with an incomplete genetic predisposition to systemic lupus erythematosus

“…Indeed, B6 mice deficient in Fc␥ receptor IIB (Fc␥RIIB) spontaneously develop circulating antichromatin and anti-dsDNA autoantibodies along with immune complex GN and pulmonary vasculitis, whereas Fc␥RIIB-deficient BALB/c mice do not (56). Moreover, B6 mice deficient in programmed death 1 (PD-1) develop a clinical phenotype highlighted by arthritis and GN (57), whereas BALB/c mice deficient in PD-1 develop no signs of arthritis or GN but do develop a lethal dilated cardiomyopathy (58). Thus, discrete immune disturbances elicit SLE-like features in B6 mice, but the identical immune disturbances do not do so in BALB/c mice.…”

Paradoxical role of programmed death‐1 ligand 2 in Th2 immune responses in vitro and in a mouse asthma model in vivo

“…The in vivo functions of PD-1, PD-L1, and PD-L2 have been of interest because PD-1 -/-mice progressively develop autoimmune diseases [12,13]. Since previous studies have shown that PD-L2 expression may be regulated in some cell types by Th2 cytokines or Th2 cells [21], and because asthma is believed to be a Th2-driven disease [23][24][25][26][27][28][29][30][31][32], it was of interest to examine whether PD-L2 can play a role in immune regulation in this context.…”

“…PD-1 has an immunoreceptor tyrosine-based inhibitory motif in its cytoplasmic domain [9][10][11]. Depending on background strain, PD-1 -/-mice develop increased rates of glomerulonephritis, lupus-like arthritis [12], or autoimmune cardiomyopathy [13]. This provides direct evidence for PD-1 as a negative regulator of immune responses in vivo [13].…”