The relative contribution of the CD28 and gp39 costimulatory pathways in the clonal expansion and pathogenic acquisition of self-reactive T cells.

Abstract

SummaryThe zona pellucida (ZP), an ovarian extracellular structure, contains three major glycoproteins: ZP1, ZP2, and ZP3. A ZP3 peptide contains both an autoimmune oophoritis-inducing T cell epitope and a B cell epitope that induces autoantibody to ZP. This study investigates two major T cell costimulation pathways in this disease model. Herein we show that blockage of glycoprotein (gp)39 and CD40 interaction with gp39 monoclonal antibody (mAb) results in the failure to induce both autoimmune oophoritis and autoantibody production. Inhibition of hgand binding to the CD28 receptor with the fusion protein, murine CTLA4-immunoglobulin (Ig), also results in failure to generate antibody to ZP and significantly reduces disease severity and prevalence. Surprisingly, the frequencies of antigen-specific T cells in anti-gp39 mAbtreated mice, CTLA4-Ig treated mice, and in mice given control hamster IgG or control fusion protein L6, were equivalent as determined by hmiting dilution analysis (--~ 1 : 5,000). These T cells, which produced comparable amounts ofinterleukin 4 and interferon ~/in vitro, were able to transfer oophoritis to normal recipients. When anti-gp39 mAb and CTLA4-Ig were given together, the effect was additive, leading to inhibition of T cell activation as determined by in vitro prohferation and bruiting dilution analysis (-~1:190,000); disease and antibody responses were absent in these mice. By studying these two costimulatory pathways in parallel, we have shown that autoimmune disease and autoantibody production are inhibitable by blocking either the gp39 or the CD28 pathway, whereas inhibition of clonal expansion of the effector T cell population occurs only when both pathways are blocked.

The role of CD40/CD154 interactions in the priming, differentiation, and effector function of helper and cytotoxic T cells

“…In light of the fact that constitutive B7 costimulation appears to restore the ability of CD154-deficient mice to prime T cells for cytokine production in some systems [31,32], it is likely that in the absence of CD40/CD154 interactions, ample B7 costimulation for initial T cell priming is present in cases such as colitis disease onset or following Leishmania infection. Consistent with this notion are numerous studies in which the immunosuppressive effects of reagents that block CD40/CD154 and CD28/B7 interactions are additive rather than redundant [45,47,59], indicating that the induction of B7 costimulatory activity after antigenic challenge is not dependent solely on CD40/CD154 interactions. Nevertheless, unlike CD40-mediated B7 molecule induction, CD40-mediated IL-12 production seems to be critical for the onset of TNBScolitis and for Leishmania immunity despite the fact that T cells of the Th2 phenotype have been primed in these cases.…”

“…For instance, studies by Griggs et al indicate that, although in vivo administration of anti-CD154 inhibits the Th1-mediated disease oophoritis, in vitro studies indicate that antigen-specific T cell expansion and cytokine production are unaffected by the antibody [59]. Thus, it appears at least in this particular system that T cell priming and effector maturation occur in the absence of CD40/CD154 costimulation.…”

“…Although CFA is a powerful adjuvant and most likely induces significant inflammation at the site of injection [60], it does not appear to allow the immune system to bypass the need for CD40/CD154 interactions for T cell priming in some systems [29]. However, in other systems recall proliferative responses appear normal in the absence of CD40/CD154 costimulation after the administration of antigen with bacterial adjuvant [31,59], suggesting that T cell priming per se is not impaired and that adjuvant can bypass the requirement for this receptor/ligand pair in some cases. During the course of an infection by a viral pathogen such as LCMV, destruction of infected tissues and the production of IFN-␥ as well as other inflammatory cytokines in response to viral replication constitutes a powerful adjuvant to the immune system and is most likely what allows for the expansion and effector maturation of CD4 ϩ and CD8 ϩ T cells in the absence of CD40/CD154 interactions [56][57][58].…”

“…For example, comparable levels of IL-4 and IFN-␥ are produced by DLN cells isolated from control or anti-CD154-treated mice after in vitro restimulation in the autoimmune oophoritis system [59]. In addition, despite the fact that anti-CD154 was shown to induce transplant engraftment, cytokine message levels for IL-2, IL-4, and IFN-␥ within heart allografts in antibody-treated mice were shown to be identical to control mice [45].…”

“…In addition to cell-mediated immunity generated against these particular viral pathogens, studies characterizing T cell responses in the autoimmune oophoritis system, a model for CD4 ϩ Th1-mediated inflammatory disease, also indicate that CD4 ϩ T cell priming can occur in the absence of CD40/CD154 interactions [59]. In this system DLN cells harvested from mice immunized with a peptide derived from an ovarian determinant in CFA and administered anti-CD154 exhibited in vitro proliferative and cytokine recall responses comparable to control mice.…”