Protective͞suppressive major histocompatibility complex (

No abstract

Because Th1/Th2 balance is perturbed during immunological disease, the design of strategies aiming at its rectification has become a priority. The alteration of the balance in pregnancy so as to promote survival of the fetal allograft lends credibility to this aim. Attenuation of the activation signal delivered through the T cell receptor (TCR) represents a promising approach. It is supported by the high level of polymorphism in the MHC class II promoter, which regulates the natural TCR signal and thus modulates Th1/Th2 differentiation. Further support comes from the Th2 shift that occurs in JNK knockout mice, and with kinase inhibitors and anti-CD4 monoclonal antibodies applied in vitro. The approach has implications for nasal tolerance and inhibition of IL-12 production. The further range of options for Th1/Th2 modulation, which are presented throughout this issue of the journal, are here summarised and evaluated.

ABSTRACTStreptococcal mitogenic exotoxin Z-2 (SMEZ-2) is a streptococcal superantigen that primarily stimulates human T cells bearing Vβ8 and mouse T cells bearing Vβ11. Mutagenesis of T cell receptor (TCR)-binding residues (W75L, K182Q, D42C) produced a mutant called M1 that was >105-fold less active toward human peripheral blood lymphocytes and splenocytes from transgenic mice that express human CD4 and either human HLA-DR3-DQ2 or HLA-DR4-DQ8. Similarly, cytokine production in response to M1 in lymphocyte culture was rendered undetectable, and no change in the frequency of Vβ11-bearing T cells in mice receiving M1 was observed. M1 toxoid was tested as a potential vaccine conjugate. Vaccination with 1 to 10 μg M1 conjugated to ovalbumin (M1-ovalbumin) resulted in more rapid and quantitatively higher levels of anti-ovalbumin IgG, with endpoint titers being 1,000- to 10,000-fold greater than those in animals immunized with unconjugated ovalbumin. Substantially higher levels of anti-ovalbumin IgG were observed in mice transgenic for human major histocompatibility complex (MHC) class II. Substitution of M1 with an MHC class II binding mutant (DM) eliminated enhanced immunity, suggesting that M1 enhanced the delivery of antigen via MHC class II-positive antigen-presenting cells that predominate within lymphoid tissue. Immunization of animals with a conjugate consisting of M1 and ovalbumin peptide from positions 323 to 339 generated levels of anti-peptide IgG 100-fold higher than those in animals immunized with peptide alone. Coupling of a TCR-defective superantigen toxoid presents a new strategy for conjugate vaccines with the additional benefit of targeted delivery to MHC class II-bearing cells.

Cytokines are the main agents known to regulate Th1 / Th2 commitment, where they may operate through paracrine activity within clusters of T cells gathered around dendritic cells (DC). An in vitro system is used here to test this possibility, using clusters around DC composed of naive TCR-transgenic ovalbumin peptide 323 - 339-specific CD4(+) T cells as targets plus TCR-transgenic pigeon cytochrome C peptide 88 - 104-specific CD4(+) polarized Th1 or Th2 cells as inducers. The polarized inducer cells exerted their maximum effect when the two T cell populations were activated within the same cluster, implemented by allowing a single DC to present both their epitopes. This finding thus supports the paracrine hypothesis. The system was then employed to explore the role of individual cytokines by means of inhibition by monoclonal antibodies. Development of Th2 commitment proved strictly dependent on the IL-4 produced by the Th2 inducers. For Th1 commitment, IFN-gamma and IL-12 were both needed, but with IFN-gamma required only during the initial period of culture. The rapid timing observed under these conditions places constraints on the molecular basis of commitment, and appears accurately to reflect the physiological response in vivo.