Reciprocal changes in tumor antigenicity and antigen-specific T cell function during tumor progression.

Two seemingly incompatible models exist to explain the progression of cancers in immunocompetent hosts. The cancer immunosurveillance hypothesis posits that recognition of transformed cells by the immune system results in the generation of an effector response that may impede tumor growth. Clinically detectable cancer results from the emergence of tumor variants that escape this selective pressure. Alternatively, induction of immune tolerance to tumor antigens may enable cancer progression. We established a model where changes in the function of tumor-specific T cells and in tumor antigen expression could be followed during cancer progression. Early recognition of antigen led to activation, expansion, and effector function in tumor-specific CD4+ T cells resulting in the outgrowth of tumors expressing substantially reduced levels of antigen. Antigen loss was not complete, however, and levels remained above the threshold required for tumor-specific T cell recognition in vivo. In the face of persisting antigen, T cell tolerance ensued, leading to an impaired ability to mediate further antigen loss. Together, these studies establish that the processes of immunosurveillance and tumor editing coexist with a process in which the functional tumor-specific T cell repertoire is also "edited," reconciling two hypotheses historically central to our attempts to understand host antitumor immunity.

Neonatal sex steroids affect responses to Seoul virus infection in male but not female Norway rats.

Previous studies illustrate that after inoculation with Seoul virus (i.e., the naturally occurring hantavirus found in Norway rats), adult male rats produce higher antibody responses, exhibit higher Th1 responses (i.e., IgG2a, IL-2, and IFN gamma), and shed virus longer than females, but these difference are not altered by manipulation of sex steroids in adulthood. To determine whether sex steroid hormones organize adult responses to hantavirus infection, at 2-4 days of age, male rats were gonadectomized and female rats were injected with testosterone. As adults, animals were inoculated with 10(4)pfu of Seoul virus. Neonatally gonadectomized males (NGM), control females (CF), and neonatal testosterone-treated females (NTF) had lower anti-Seoul virus IgG and IgG2a responses than control males (CM) 20, 30, and 40 days post-inoculation. Neonatal testosterone treatment had no effect on female antibody responses to infection. NGM, CF, and NTF shed virus in saliva and feces for a shorter duration than CM. There was no effect of neonatal hormone manipulation either on the percentage of animals with detectable virus or on the number of virus copies within each target organ. Genetic males, regardless of hormone manipulation, had higher virus replication in lung tissue than did genetic females. Neonatal sex steroids influence the sexual dimorphism in host immune function but do not modify virus replication in target tissues.

Early exposure to genistein exerts long-lasting effects on the endocrine and immune systems in rats.

BACKGROUND: Although the immunologic effects of endogenous and synthetic estrogens are well studied, few studies have examined the hormonal effects of phytoestrogens (i.e., plant-derived estrogens) on the immune system. The primary goal of this study was to compare the effects of perinatal exposure with life-long exposure to genistein, an estrogenic compound in soy, on the endocrine and immune system in adulthood. MATERIALS AND METHODS: Pregnant female rats were exposed to no, low (5 mg/kg diet), or high (300 mg/kg diet) genistein diets throughout gestation and lactation. At weaning, male offspring exposed to genistein perinatally were either switched to the genistein-free diet or remained on the genistein-dosed diets. At 70 days of age, immune organ masses, lymphocyte subpopulations, cytokine concentrations, and testosterone concentrations were assessed in male offspring. RESULTS: Data were analyzed based on the diets that males were exposed to during gestation and lactation because life-long exposure to genistein had no additional effect on any of the dependent measures. Relative thymus masses were greater among males exposed to the high genistein diet than among males exposed to no genistein. Although the proportions of splenic and thymic CD4+ T cells were not altered by genistein, the percentages of CD4+CD8+ thymocytes, CD8+ splenocytes, and total T cells in the spleen were higher and the percentages of CD4-CD8- thymocytes were lower among males exposed to genistein than among males not exposed to genistein. Synthesis of interferon-gamma (IFN-gamma) was marginally higher and testosterone concentrations were lower among genistein-exposed than genistein-free males. DISCUSSION: These data illustrate that exposure to genistein during pregnancy and lactation exerts long-lasting effects on the endocrine and immune systems in adulthood. Whether exposure to phytoestrogens during early development affects responses to infectious or autoimmune diseases, as well as cancers, later in life requires investigation.

Role of LAG-3 in regulatory T cells.

Regulatory T cells (Tregs) limit autoimmunity but also attenuate the magnitude of antipathogen and antitumor immunity. Understanding the mechanism of Treg function and therapeutic manipulation of Tregs in vivo requires identification of Treg-selective receptors. A comparative analysis of gene expression arrays from antigen-specific CD4(+) T cells differentiating to either an effector/memory or a regulatory phenotype revealed Treg-selective expression of LAG-3, a CD4-related molecule that binds MHC class II. Antibodies to LAG-3 inhibit suppression by induced Tregs both in vitro and in vivo. Natural CD4(+)CD25(+) Tregs express LAG-3 upon activation, which is significantly enhanced in the presence of effector cells, whereas CD4(+)CD25(+) Tregs from LAG-3(-/-) mice exhibit reduced regulatory activity. Lastly, ectopic expression of LAG-3 on CD4(+) T cells significantly reduces their proliferative capacity and confers on them suppressor activity toward effector T cells. We propose that LAG-3 marks regulatory T cell populations and contributes to their suppressor activity.