Prevention of spontaneous arthritis by inhibiting homeostatic expansion of autoreactive T cells in K/BxN mice

Abstract

Although lymphopenia has been shown to correlate with several autoimmune diseases including rheumatoid arthritis, the mechanism by which lymphopenia causes autoimmunity remains elusive in the instance of rheumatoid arthritis. We determined whether compensatory homeostatic expansion of autoreactive T cells during immune insufficiency can precipitate disease in a glucose-6 phosphate isomerase (GPI)-specific TCR transgenic mouse model named K/BxN. These lymphopenic mice spontaneously developed arthritis at about 4 weeks of age, which was associated with the development of GPI-specific T and B cells. To inhibit homeostatic expansion by preoccupying available space in lymphoid organs, K/BxN mice in a pre-clinical stage were infused with syngeneic lymph node cells or immunized with complete Freund`s adjuvant. After these treatments, K/BxN mice exhibited a dramatic decrease in the incidence and severity of arthritis, compared with untreated mice. This reduction was correlated with reduced GPI-specific T cell numbers and GPI-specific antibody levels. To eliminate the possibility that regulatory T cells contained in syngeneic donor cells might contribute to the suppression of arthritis development, CD25+ cell-depleted lymph node cells were adoptively transferred to K/BxN mice. CD25+ T cell depletion did not abolish the suppressive effect of infused cells, indicating that conventional lymphocyte transfer rather than the action of CD25+ regulatory T cells played a role in the suppression of disease. These data provide the first evidence that inhibition of homeostatic proliferation of autoreactive T cells protects mice from initiating autoimmune arthritis.