Biological characteristics of an immunoregulatory activity secreted by an autoreactive CD4⁺ T cell clone that suppresses autoimmune diabetes in non-obese diabetic mice

Abstract

We previously reported the generation and characterization of a panel of CD4(+) autoreactive T cell clones that suppress development of autoimmune diabetes in non-obese diabetic (NOD) mice. We showed that the protective capacity of the T cell clones correlated with secretion of an activity that potently inhibits allogeneic mixed lymphocyte reaction (allo-MLR). In this report, we describe the biological characteristics of the allo-MLR inhibitory activity (MLR-IA, short for mixed lymphocyte reaction inhibitory activity) secreted by the protective T cell clone, NOD-5. MLR-IA has little effect on initiation of proliferation in an allo-MLR, but it potently inhibits the maintenance and amplification of the proliferative response. MLR-IA is also capable of inhibiting concanavalin A (Con A) stimulated splenic responder T cell proliferation. MLR-IA is reversible in vitro and is not restricted by MHC class I or II proteins. MLR-IA does not affect IL-2 receptor expression of responding T cells and has no effect on IL-2-dependent proliferation of CTLL-20 T cells. Partially purified MLR-IA inhibits IL-2 production in a primary allo-MLR, and decreases IFN-gamma production during secondary allo-MLR and Con A activation, whereas it enhances IL-4 production in both primary and secondary Con A activation. MLR-IA is not neutralized by combination of antibodies specific for transforming growth factor-beta, IL-10, tumor necrosis factor-alpha/beta or IFN-gamma, suggestive of a novel activity. MLR-IA is ammonium sulfate precipitable, sensitive to protease digestion and is destroyed by boiling, indicating that a protein moiety is part of its active structure. Our work suggests that a potentially novel immunoregulatory activity, capable of inhibiting T lymphocyte proliferation and IFN-gamma production, and stimulating IL-4 production, may regulate development of autoimmune diabetes in NOD mice.

The Nonobese Diabetic Mouse as a Model of Autoimmune Diabetes: Immune Dysregulation Gets the NOD

“…Wegmann, 1996) and spleen-derived insulin-reactive Th1 cells (Daniel and Wegmann, 1996) can transfer Thus, a relative lack of IL-4 production by NK-T cells is associated with and may be causal to the onset of IDDM, islet-derived CD4 ϩ Th1 cells can also prevent IDDM (Chosich and Harrison, 1993;Akhtar et al, 1995; IDDM. This idea is further supported by the decreased frequency of IL-4-producing NK-T cells and the impaired Tan et al, 1996). Similarly, while IL-4-secreting Th2 cells (Bergerot et al, 1994;Ploix et al, 1997) and/or Th3 cells IL-4 production by circulating T cells in the peripheral blood of patients with IDDM (Berman et al, 1996; Wilson (secreting IL-4, IL-10, and transforming growth factor-␤) obtained from the intestinal mucosa of oral insulin-fed et al, 1997).…”

Engineering mouse T lymphocytes specific to type II collagen by transduction with a chimeric receptor consisting of a single chain Fv and TCR zeta

“…16,17 Cloned Th2 cells also reduced inflammatory reaction in some of these cell-mediated autoimmune diseases as long as these cells were autoantigen specific. [18][19][20][21][22] CII is a tissue-specific protein in articular cartilage and one of the candidate autoantigens in rheumatoid arthritis. Induction of humoral and cellular immune response to CII leads to the development of CIA in mice.…”