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It is well established that interactions between CD4+ T cells and major histocompatibility complex class II ( MHCII) positive antigen-presenting cells ( APCs) of hematopoietic origin play key roles in both the maintenance of tolerance and the initiation and development of autoimmune and inflammatory disorders. In sharp contrast, despite nearly three decades of intensive research, the functional relevance of MHCII expression by non-hematopoietic tissue-resident cells has remained obscure. The widespread assumption that MHCII expression by non-hematopoietic APCs has an impact on autoimmune and inflammatory diseases has in most instances neither been confirmed nor excluded by indisputable in vivo data. Here we review and put into perspective conflicting in vitro and in vivo results on the putative impact of MHCII expression by non-hematopoietic APCs-in both target organs and secondary lymphoid tissues-on the initiation and development of representative autoimmune and inflammatory disorders. Emphasis will be placed on the lacunar status of our knowledge in this field. We also discuss new mouse models-developed on the basis of our understanding of the molecular mechanisms that regulate MHCII expression-that constitute valuable tools for filling the severe gaps in our knowledge on the functions of non-hematopoietic APCs in inflammatory conditions. [ABSTRACT FROM AUTHOR]

Injection of cells expressing the retroviral superantigen Mls-1 (Mtv-7 sag) into adult Mls-1 — mice induces a strong immune response including both T- and B-cell activation. This model was used for studying qualitative aspects of the immune response in normal mice with a defined antigen-presenting cell (the B cell) and without the use of adjuvant. BALB/c mice were injected locally or systemically with Mis-l-expressing spleen cells from Mis-l-congenic BALB.D2 mice. Intravenous injection led to an initially strong expansion of Mis-l-reactive Vβ6+ CD4+ cells mainly in the spleen, to a large degree explained by the trapping of reactive cells, and a rapid down-regulation of interleukin-2 (IL-2) and interferon-γ (IFN-γ) production, consistent with the proposed tolerogenic property of B cells as antigen-presenting cells. However, these mice developed a slowly appearing but persistent B-cell response dominated by IgG1-producing cells, suggesting a shift in lymphokines produced rather than complete unresponsiveness. Subcutaneous injection into the hind footpad with the same number of cells led to a strong local response in the draining lymph node, characterized by a dramatic increase of Vβ6+ CD4+ T cells, local production of IL-2 and IFN-γ, and a strong but short-lived antibody response dominated by IgG2a-producing cells, characteristic of a T-helper type 1 (Th 1) type of response. Both routes of injection led ultimately to deletion of reactive T cells and anergy, as defined by the inability to produce IL-2 upon in vitro stimulation with Mis-1. It is concluded that Mls-1 presented by B cells induces qualitatively different responses in vivo dependent on the route of injection. We propose that the different responses result from the migration of the injected cells to different micro-anatomical sites in the lymphoid tissue. Furthermore, these results suggest that B cells may function as professional antigen-presenting cells in vivo if present in an appropriate environment. [ABSTRACT FROM AUTHOR]

The non-obese diabetic (NOD) mouse is a model for the study of insulin-dependent diabetes mellitus (IDDM). Recently transgenic NOD mice have been derived (NOD-E) that express the major histocompatibility complex (MHC) class III-E molecule. NOD-E do not become diabetic and show negligible pancreatic insulins. The possibility pertained that NOD-E mice are protected from disease by a process of T-cell deletion or anergy. This paper describes our attempts to discover whether this was so, by comparing NOD and NOD-E mouse T-cell receptor Vβ usage. Splenocytes and lymph node cells were therefore tested for their ability to proliferate iii response to monoclonal anti-Vβ antibodies. We were unable to show any consistent differences between NOD and NOD-E responses to the panel of antibodies used. Previously proposed Vβ were shown to be unlikely candidates for deletion or anergy. T cells present at low frequency (Vβ5+) in both NOD and NOD-E mice were shown to be as capable of expansion in response to antigenic stimulation as were more frequently expressed Vβ. Our data therefore do not support deletion or anergy as mechanisms which could account for the observed disease protection in NOD-E mice. [ABSTRACT FROM AUTHOR]