Costimulation Requirements of Induced Murine Systemic Autoimmune Disease

Abstract

Costimulation between T cells and APC is required for productive immune responses. A number of receptor/ligand pairs have been shown to mediate costimulation, including CD28/B7 molecules (CD80 and CD86), CD40/CD40 ligand (CD40L, CD154), and LFA-1 (CD18)/ICAM-1 (CD54). T-B cell costimulation also plays a significant role in autoimmune diseases such as systemic lupus erythematosus. Murine HgCl2-induced autoimmunity (mHgIA) is a T cell-dependent systemic autoimmune disease that shares a number of common pathogenic mechanisms with idiopathic lupus. In this report, the significance of costimulation in mHgIA is examined by attempting to induce disease in mice deficient in either CD40L, CD28, or ICAM-1. Unlike absence of ICAM-1, homozygous deficiencies in either CD40L or CD28 significantly reduced the development of mHgIA. CD40L displayed a gene dosage effect as heterozygous mice also showed reduction of autoantibody responses and immunopathology. Markers of T cell activation such as CD44 and CTLA-4 were associated with disease expression in wild-type and ICAM-1-deficient mice but not in CD40L- or CD28-deficient mice. Absence of CTLA-4 expression in CD40L−/− mice suggests that signaling via both CD28 and CD40L is important for T cell activation and subsequent autoimmunity in mHgIA. Attempts to circumvent the absence of CD40L by increasing CD28 signaling via agonistic Ab failed to elicit CTLA-4 expression. These findings indicate that breaking of self-tolerance in mHgIA requires signaling via both the CD28/B7 and CD40/CD40L pathways.

A Costimulatory Function for T Cell CD40

“…This has been demonstrated in the experimental autoimmune encephalomyelitis model of multiple sclerosis, whereby disease development is dependent on CD40 signaling, particularly in the absence of CD28 (96). In the HgCl 2 -induced autoimmunity model, CD28 is unable to overcome the lack of CD40 signaling to induce disease (97).…”

“…5). Increased levels of not only CD40, but other costimulatory molecules such as CD80, CD86, ICAM-1, and LFA-1, may also be pivotal in autoimmune disease development (97). Although beyond the scope of this study, it would be interesting to investigate the costimulatory capacity of activated CD40-expressing T cells for CD40-negative T cells, as well as for other cell types, including APC.…”

Depletion of complement does not impact initiation of xenobiotic‐induced autoimmune disease

“…15 However, mHgIA is initiated in the absence of IL-4 16,17 but interferon-c (IFN-c) is required. 16 Development of mHgIA has been found to require both the CD28/B7 and CD40/CD40 ligand T-cell co-stimulation pathways 18 and to be exacerbated by the absence of Daf1. 19 We have recently demonstrated in mHgIA that mRNA and protein expression of Daf1 is reduced in splenic CD4 + T cells with an activated/memory phenotype and that accumulation of CD44…”

“…Mice were injected subcutaneously (s.c.) twice per week for 1 or 2 weeks with 40 lg mercuric chloride (HgCl 2 ; Mallinckrodt Baker Inc, Phillipsburg NJ) in PBS (pH 7Á4) as previously described 18 and killed by halothane anaesthesia (Halocarbon Labs, River Edge, NJ) before cervical dislocation 3 days after the final injection in the 1-week or 2-week regimens. Controls received PBS alone.…”

“…20 These CD44 high /Daf low CD4 + T cells produced elevated levels of IL-4, 20 a cytokine associated with active mHgIA. 15,16,40 The importance of the downregulation of Daf1 to the autoimmune response was further demonstrated with DBA/2 and CD28-deficient B10.S mice, which are resistant to mHgIA, 18,41 have no change in Daf1 levels and do not exhibit T-cell activation or accumulation following exposure to mercury. 20 Most recently, Daf1 deficiency in C57BL/6 mice has been argued to result in age-related autoimmunity, including lymphadenopathy, splenomegaly and anti-chromatin autoantibodies, and dermatitis.…”