Soluble Costimulatory Molecules Research Articles

Elevation of Plasma Soluble T Cell Costimulatory Molecules CTLA-4, CD28 and CD80 in Children with Allergic Asthma

Background: The surface expression of T cell costimulatory molecules CTLA-4 and CD28 and their counter-ligands, B7 molecules (CD80, CD86), is differentially induced for T cell activation and expansion in allergic asthma. However, the role of their soluble forms in plasma has not yet been elucidated. In this study, we investigated whether expression is altered and whether soluble costimulatory molecules are clinically relevant in asthmatic patients. Methods: Plasma concentrations of soluble CTLA-4 (sCTLA-4), CD28, CD80 and CD86 in 51 children with chronic allergic asthma with or without inhaled corticosteroid treatment, and 22 sex- and age-matched control subjects were measured by enzyme-linked immunosorbent assay. Plasma total IgE concentration was measured using a microparticle immunoassay. Results: Asthmatic patients had higher logarithmic plasma total IgE concentration (IgE_log) than healthy subjects (p < 0.0001). In non-steroid-treated patients, plasma sCTLA-4, sCD28 and sCD80 but not sCD86 concentrations were significantly higher than those of control subjects (all p < 0.05). Plasma sCD80 and sCD86 but not sCTLA-4 and sCD28 concentrations correlated significantly with IgE_log of all subjects (p < 0.05). There were also significant positive correlations between sCTLA-4 and sCD28 (p = 0.0007), and between sCD80 and sCD86 in all asthmatic patients (p = 0.001). Conclusions: Plasma sCTLA-4, sCD28 and sCD80 concentrations are elevated in allergic asthma. The increased expression of these soluble proteins may reflect the dysregulation of T cell activation, contributing to the immunopathogenesis of allergic asthma.

Antigen delivery systems and immunostimulation

The immune system evolved to free the host from invading noxious pathogens. Vaccines are inoculated as a prophylactic measure in order to program the immune system for accelerated recognition and elimination of specific pathogens. During vaccination the immune system is exposed to attenuated or inactivated microorganisms, or their fragments. The immune response to these structures, in contrast to virulent pathogens, is often inadequate for the generation of memory cells or immune effector elements such as antibodies, perforines, granzymes or cytokines. Vaccine adjuvants help to overcome these limited responses. They provide instructive signals for the host immune system by mimicking the conditions associated with virulent infection. Hence, they either enhance and prolong expression of antigen components to reactive T cells in lymph nodes (signal 1) or they increase expression of membrane-bound or soluble costimulatory molecules (signal 2). The enhancement of both signals by vaccine adjuvants is not mutually exclusive. Moreover, adjuvants may encode a third signal instructing the type of immune reaction to be generated. Supported by animations this presentation addresses putative immunological concepts of vaccine adjuvant activity, a phenomenon long been known as “the immunologist’s dirty little secret”. Insight in the mechanisms that underlie adjuvant-induced immunostimulation and generation of memory cells will facilitate rational vaccine design.

Alloantigen presentation to naive CD8+ T cells by mouse microglia: evidence for a distinct phenotype based on expression of surface-associated and soluble costimulatory molecules.

We previously showed that approximately one-third of mouse primary microglial clones derived from individual precursor cells residing in normal brain constitutively present alloantigens (alloAgs) to naive CD8+ T cells (Moore et al.: J Neuroimmunol 41:203, 1992). To understand the basis for this alloAg presenting (alloAgP) activity, we developed a panel of microglial cell lines that were characterized by patterns of alloAgP activity similar to that of the primary clones. Flow cytometric analysis revealed that microglia with and without alloAgP activity expressed similar levels of major histocompatibility complex class I molecules; however, CD80 (B7-1) and CD86 (B7-2) expression was primarily restricted to the alloAgP- cell lines. Monoclonal antibody (Mab) to CD80 only partially blocked the proliferative response of allogeneic CD8+ T cells cocultured with the presenting cell lines, whereas Mab to CD86 completely inhibited the response, indicating a significant role for this molecule in T-cell activation. Using an immunoassay, recombinant mouse cytokines, cytokine-specific Mabs, and the reverse transcriptase-polymerase chain reaction to detect specific cytokine mRNAs, we found the synthesis of interleukin (IL)-1 alpha, IL-6, IL-12, and tumor necrosis factor-alpha (TNF-alpha) to be restricted to the alloAgP- cell lines. Costimulatory roles were then identified for these molecules. We conclude that the ability to present alloAg is a property of a subset of microglia that constitutively express CD86 and secrete costimulatory cytokines that promote the expansion of the alloAg-stimulated CD8+ T cells.