Juvenile diabetes (type 1) is an autoimmune disease in which CD4 ؉ T cells play a major role in pathogenesis characterized by insulitis and ␤ cell destruction leading to clinical hyperglycemia. To date, no marker for autoimmune T cells has been described, although it was previously demonstrated that autoimmune mice have a large population of CD4 ؉ cells that express CD40. We show here that established, diabetogenic T cell clones of either the Th1 or Th2 phenotype are CD40-positive, whereas nondiabetogenic clones are CD40-negative. CD40 functionally signals T cell clones, inducing rapid activation of the transcription factor NFB. We show that autoimmune diabetes-prone nonobese diabetic mice have high levels of CD40 ؉ CD4 ؉ T cells in the thymus, spleen, and importantly, in the pancreas. Finally, as demonstrated by adoptive transfers, CD4 ؉ CD40 ؉ cells infiltrate the pancreatic islets causing ␤-cell degranulation and ultimately diabetes.

Physical restraint (RST) was used to examine the interactions among the hypothalamic-pituitaryadrenal (HFA) axis, sympathetic nervous system, and the immune response to infection. In these studies, mice were infected with either herpes simplex virus (HSV) or influenza A/PR8 virus so that the impact of neuroendocrine activation could be assessed on disease pathophysiology and anti-viral immunity. RST suppressed lymphadenopathy in draining lymph nodes, reduced mononuclear cellular infiltration in the lungs, and suppressed virus-specific cytokine and cytolytic T-cell responses. Blockade of type II glucocorticoid receptors (by RU486) restored cellularity and cytokine responses to both organs in restraint-stressed, infected mice. Thus, the HPA axis modulated cell trafficking and T-cell cytokine responses. However, RU486 treatment failed to restore cytolytic Tcell responses. Blockade of β-adrenergic receptors (by nadolol), in combination with RU486 treatment, fully restored cytolytic T-cell responses, suggesting that catecholamines were involved in suppressing the virus-specific CD8 + cytolytic T-cell response. RST also modulated the local development or expression of antibody-secreting cells (ASC) in the lungs draining lymph nodes, and spleen following infection of restrained mice. RST significantly suppressed the number of virusspecific ASC (IgM, IgG and subclasses IgG1 and IgG2a) in the lungs, mediastinal (MLN) lymph nodes and spleen, while it enhanced the responses in the superficial cervical (SCV) lymph nodes. This observation of differential modulation of ASC responses in the MLN and SCV lymph nodes supports the concept of tissue-specific immunoregulation in response to stress. The host's response to a viral infection is designed to limit the initial spread of the pathogen and then terminate its replication. Innate host mechanisms, such as natural killer (NK) cell activity and proinflammatory cytokines (IL-1, IL-6, and TNF), along with the α and β interferons, function in the early hours of infection to limit the spread of virus. These noncognate responses, however, usually are not sufficient to end viral replication. Therefore, adaptive host responses occur that take days to weeks to mature. These adaptive responses promote the entry of antigen-specific lymphocytes into the cell cycle and result in clonal selection, proliferation, and maturation to the effector stage. Because many viruses are tropic to and replicate in nonlymphoid tissues, effector cells must traffic to the site of virus replication to effectively eliminate the pathogen.

The mammalian response to stress involves the release of soluble products from the sympathetic nervous system and the hypothalamic-pituitary-adrenal axis. Cells of the immune system respond to many of the hormones, neurotransmitters, and neuropeptides through specific receptors. The function of the immune system is critical in the mammalian response to infectious disease. A growing body of evidence identifies stress as a cofactor in infectious disease susceptibility and outcomes. It has been suggested that effects of stress on the immune system may mediate the relationship between stress and infectious disease. This article reviews recent psychoneuroimmunology literature exploring the effects of stress on the pathogenesis of, and immune response to, infectious disease in mammals.

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To detect and characterize autoreactive T cells in diabetes-prone NOD mice, we have developed a multimeric MHC reagent with high affinity for the BDC-2.5 T cell receptor, which is reactive against a pancreatic autoantigen. A distinct population of T cells is detected in NOD mice that recognizes the same MHC/peptide target. These T cells are positively selected in the thymus at a surprisingly high frequency and exported to the periphery. They are activated specifically in the pancreatic LNs, demonstrating an autoimmune specificity that recapitulates that of the BDC-2.5 cell. These phenomena are also observed in mouse lines that share with NOD the H-2 g7 MHC haplotype but carry diabetes-resistance background genes. Thus, a susceptible haplotype at the MHC seems to be the only element required for the selection and emergence of autoreactive T cells, without requiring other diabetogenic loci from the NOD genome.

To detect and characterize autoreactive T cells in diabetes-prone NOD mice, we have developed a multimeric MHC reagent with high affinity for the BDC-2.5 T cell receptor, which is reactive against a pancreatic autoantigen. A distinct population of T cells is detected in NOD mice that recognizes the same MHC/peptide target. These T cells are positively selected in the thymus at a surprisingly high frequency and exported to the periphery. They are activated specifically in the pancreatic LNs, demonstrating an autoimmune specificity that recapitulates that of the BDC-2.5 cell. These phenomena are also observed in mouse lines that share with NOD the H-2 g7 MHC haplotype but carry diabetes-resistance background genes. Thus, a susceptible haplotype at the MHC seems to be the only element required for the selection and emergence of autoreactive T cells, without requiring other diabetogenic loci from the NOD genome.

SUMMARY:Islet-specific T cells are essential in the development of type I diabetes. The role of non-lymphoid cells is relatively unclear, although infiltration of dendritic cells and macrophages is the first sign of islet autoimmunity in diabetes-prone nonobese diabetic (NOD) mice. BDC2.5 is one of the autoreactive T cell clones isolated from NOD mice. Transfer of BDC2.5 T cells into young NOD mice accelerates diabetes development, whereas transgenic expression of the BDC2.5 T cell receptor on NOD T cells (BDC2.5 TCR-Tg NOD) markedly reduces diabetes development. We show that, although the same antigen-specificity is involved, both models differ significantly in insulitis. BDC2.5 TCR-Tg NOD mice develop an extensive, but non-aggressive, peri-insulitis by 3 weeks of age. In these large peri-islet infiltrates, resembling secondary lymphoid tissue, BM8 ϩ macrophages (M) are virtually absent. In contrast, BDC2.5 T cell clone transfer results in an aggressive insulitis with small infiltrates, but relatively large numbers of BM8 ϩ M. Infiltration of BM8 ϩ M therefore correlates with islet destruction. This is, however, not observed for all M; Monts-4 ϩ M follow a reverse pattern and are present in higher numbers in BDC2.5 TCR-Tg than in transferred mice. ER-MP23 ϩ M are reduced in both transferred and transgenic mice compared with wild-type NOD. Thus, this study underlines and extends previous data suggesting that M are implicated in both early and late phases in diabetes development. Furthermore, our data imply that subsets of non-lymphoid cells have different roles in diabetes development. It is, therefore, important to recognize this heterogeneity when interpreting both in vivo and in vitro studies concerning non-lymphoid cells in diabetes. (Lab Invest 2000, 80:23-30).

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