Immunological Switch Research Articles

Mechanisms underlying aryl hydrocarbon receptor-driven divergent macrophage function.

Macrophages play an essential role in the innate immune system by differentiating into functionally diverse subsets in order to fight infection, repair damaged tissues, and regulate inappropriate immune responses. This functional diversity stems from their ability to adapt and respond to signals in the environment, which is in part mediated through aryl hydrocarbon receptor (AHR)-signaling. AHR, an environmental sensor, can be activated by various ligands, ranging from environmental contaminants to microbially derived tryptophan metabolites. This review discusses what is currently known about how AHR-signaling influences macrophage differentiation, polarization, and function. By discussing studies that are both consistent and divergent, our goal is to highlight the need for future research on the mechanisms by which AHR acts as an immunological switch in macrophages. Ultimately, understanding the contexts in which AHR-signaling promotes and/or inhibits differentiation, proinflammatory functions, and immunoregulatory functions, will help uncover functional predictions of immunotoxicity following exposure to environmental chemicals as well as better design AHR-targeted immunotherapies.

Knockout CD73 reduces thymus-derived lymphocytes and clinical phenotype of Foxp3 +Treg deficient autoimmune scurfy mice

Abstract CD73 is ubiquitously expressed and regulates critical functions across multiple organ systems. The combination of CD39 and CD73 degrade ATP to adenosine that shifts ATP-driven pro-inflammatory immune cell activity toward an anti-inflammatory state. This immunological switch is a major mechanism for Tregs to control inflammation. In the Foxp3 +Treg deficient scurfy (SF) mouse, a mouse model of human IPEX syndrome, we showed that a specific probiotic exhibits therapeutic effects via probiotic-derived adenosine. We generated CD73KOSF mice by removing host CD73, aiming to identify a specific probiotic-CD73 effect. CD73KOSF mice were generated by breeding heterozygous-Foxp3sf/J females to CD73KO male mice with genotyping confirmation. We unexpectedly observed that KO of CD73 in SF mice reduced clinical severity. CD73KOSF mice showed reduced ear thickness, increased ear size, improved deformed ears, and reduced scurfy skin compared to SF mice. SF mice had increased CD4 +and CD8 +T cells compared to WT mice; KO of CD73 in SF mice significantly reduced the numbers of these cells in the spleen and blood to normal. However, the inflammatory cytokines and chemokines in plasma and lymphocyte infiltration in the liver of CD73KOSF were similar to those in SF mice. We further identified that KO of CD73 in SF mice reduced the numbers of CD3 +T and DP CD4 +CD8 +T cells in the thymus compared to those in SF mice, indicating that reducing clinical phenotype specifically scurfy tails and deformed ears may mainly be due to reduced central and peripheral lymphoproliferation. This study provides data to aid further discovery of CD73 as a target to improve dermatitis-one of the most common symptoms in Treg-deficiency-associated primary immune deficiencies. Supported by grants from NIH/NIAID (R03AI153725)

Enhancement of immune surveillance in breast cancer by targeting hypoxic tumor endothelium: Can it be an immunological switch point?

Breast cancer ranks second among the causes of cancer-related deaths in women. In spite of the recent advances achieved in the diagnosis and treatment of breast cancer, further study is required to overcome the risk of cancer resistance to treatment and thereby improve the prognosis of individuals with advanced-stage breast cancer. The existence of a hypoxic microenvironment is a well-known event in the development of mutagenesis and rapid proliferation of cancer cells. Tumor cells, purposefully cause local hypoxia in order to induce angiogenesis and growth factors that promote tumor growth and metastatic characteristics, while healthy tissue surrounding the tumor suffers damage or mutate. It has been found that these settings with low oxygen levels cause immunosuppression and a lack of immune surveillance by reducing the activation and recruitment of tumor infiltrating leukocytes (TILs). The immune system is further suppressed by hypoxic tumor endothelium through a variety of ways, which creates an immunosuppressive milieu in the tumor microenvironment. Non responsiveness of tumor endothelium to inflammatory signals or endothelial anergy exclude effector T cells from the tumor milieu. Expression of endothelial specific antigens and immunoinhibitory molecules like Programmed death ligand 1,2 (PDL-1, 2) and T cell immunoglobulin and mucin-domain containing-3 (TIM-3) by tumor endothelium adds fuel to the fire by inhibiting T lymphocytes while promoting regulatory T cells. The hypoxic microenvironment in turn recruits Myeloid Derived Suppressor Cells (MDSCs), Tumor Associated Macrophages (TAMs) and T regulatory cells (Treg). The structure and function of newly generated blood vessels within tumors, on the other hand, are aberrant, lacking the specific organization of normal tissue vasculature. Vascular normalisation may work for a variety of tumour types and show to be an advantageous complement to immunotherapy for improving tumour access. By enhancing immune response in the hypoxic tumor microenvironment, via immune-herbal therapeutic and immune-nutraceuticals based approaches that leverage immunological evasion of tumor, will be briefly reviewed in this article. Whether these tactics may be the game changer for emerging immunological switch point to attenuate the breast cancer growth and prevent metastatic cell division, is the key concern of the current study.

Phenotype of CD39/CD73 expressed on T cells in a mouse model of IPEX syndrome

Abstract The combination of CD39 and CD73 degrade ATP to adenosine that shifts ATP-driven pro-inflammatory immune cell activity toward an anti-inflammatory state. This immunological switch is a major mechanism for regulatory T cells (Tregs) to control inflammation. However, in Treg-deficiency-induced autoimmune pathologies, exemplified by IPEX syndrome (immune dysregulation, polyendocrinopathy, enteropathy, with X-linked inheritance, as modeled by the scurfy (SF) mouse), the expression of these molecules on T cells is unknown. We analyzed homeostatic markers CD39 and CD73 on T cells in spleen and peripheral blood by flow cytometry in SF males and their sibling WT male mice at d21. Among Foxp3+ Tregs in WT mice, ~68% cells had CD39 and 85% cells had CD73 expression. In the spleens of SF mice, the % of CD39+CD4+ T cells was higher than the % in WT mice, while no difference was observed in the CD73+CD4+ T cells. In addition, the data showed ~70% of NonTregs expressed CD39, 2-fold higher than both % of CD73+ NonTregs in SF, and % of CD39+ NonTregs in WT. Only ~10% of these CD39+ and CD73+ NonTregs had the CD25 expression. The proportion of CD8+ T cells in splenocytes and blood of SF mice were significantly higher than those in WT mice. Amongst CD8+ T cells, the % of CD39+ T cells was significantly increased, conversely, the % of CD73+ T cells was significantly decreased in SF compared to WT mice. We conclude that normally, CD73 is a more highly expressed Treg surface marker than CD39; however, in Treg-deficiency, there is a higher expression by CD4+ T and CD8+ T cells of CD39 than CD73; and CD39 and CD73 expression may not be due to cell activation. This study provides data to aid further discovery of potential biomarkers and therapeutic targets in Treg deficiency diseases. Supported by grants from NIH/NIAID (R03AI153725)

Parvovirus-Based Combinatorial Immunotherapy: A Reinforced Therapeutic Strategy against Poor-Prognosis Solid Cancers.

Simple SummaryOncolytic virotherapy using oncolytic viruses with natural or engineered cancer-destroying capacities has emerged as a promising treatment concept in modern oncology. Rodent protoparvoviruses, in particular the rat H-1 parvovirus (H-1PV), have demonstrated their broad-range tumor-suppressive properties in both preclinical models and clinical studies. In addition to inducing selective tumor cell death, these viruses are also able to exert immunostimulating effects and reverse tumor-driven immune suppression. Parvovirotherapy holds therefore a potential for enhancing the efficacy of other cancer immunotherapies. The aim of this review is to provide an overview of all H-1PV-based combinatorial immunotherapeutic approaches against poor-prognosis human solid cancers that have been tested so far. Current challenges and future prospects of parvoviro-immunotherapy, notably parvovirus inclusion into various immunotherapeutic protocols against glioblastoma, pancreatic cancer, among other standard therapy-refractory solid malignancies, are also discussed in the light of H-1PV further clinical development.Resistance to anticancer treatments poses continuing challenges to oncology researchers and clinicians. The underlying mechanisms are complex and multifactorial. However, the immunologically “cold” tumor microenvironment (TME) has recently emerged as one of the critical players in cancer progression and therapeutic resistance. Therefore, TME modulation through induction of an immunological switch towards inflammation (“warming up”) is among the leading approaches in modern oncology. Oncolytic viruses (OVs) are seen today not merely as tumor cell-killing (oncolytic) agents, but also as cancer therapeutics with multimodal antitumor action. Due to their intrinsic or engineered capacity for overcoming immune escape mechanisms, warming up the TME and promoting antitumor immune responses, OVs hold the potential for creating a proinflammatory background, which may in turn facilitate the action of other (immunomodulating) drugs. The latter provides the basis for the development of OV-based immunostimulatory anticancer combinations. This review deals with the smallest among all OVs, the H-1 parvovirus (H-1PV), and focuses on H-1PV-based combinatorial approaches, whose efficiency has been proven in preclinical and/or clinical settings. Special focus is given to cancer types with the most devastating impact on life expectancy that urgently call for novel therapies.

IFNγ-activated dermal lymphatic vessels inhibit cytotoxic T cells in melanoma and inflamed skin.

Mechanisms of immune suppression in peripheral tissues counteract protective immunity to prevent immunopathology and are coopted by tumors for immune evasion. While lymphatic vessels facilitate T cell priming, they also exert immune suppressive effects in lymph nodes at steady-state. Therefore, we hypothesized that peripheral lymphatic vessels acquire suppressive mechanisms to limit local effector CD8+ T cell accumulation in murine skin. We demonstrate that nonhematopoietic PD-L1 is largely expressed by lymphatic and blood endothelial cells and limits CD8+ T cell accumulation in tumor microenvironments. IFNγ produced by tissue-infiltrating, antigen-specific CD8+ T cells, which are in close proximity to tumor-associated lymphatic vessels, is sufficient to induce lymphatic vessel PD-L1 expression. Disruption of IFNγ-dependent crosstalk through lymphatic-specific loss of IFNγR boosts T cell accumulation in infected and malignant skin leading to increased viral pathology and tumor control, respectively. Consequently, we identify IFNγR as an immunological switch in lymphatic vessels that balances protective immunity and immunopathology leading to adaptive immune resistance in melanoma.

Role of cluster of differentiation 39 (CD39) in the immunosuppressive status associated Acute myeloid leukemia (AML)

Background: CD39 is an integral membrane protein (ectoenzyeme) that phosphohydrolyzes ATP in a Ca2+- and Mg2+-dependent fashion to yield AMP, Can be viewed as immunological switch, and is expressed in spleen, thymus, lung, and placenta, and in these organs it is associated primarily with endothelial cells and immune cell populations, such as B cells, NK cells, dendritic cells, Langerhans cells, monocytes, macrophages, mesangial cells, neutrophils, and regulatory T cells. Aim of the study is to assess the expression of CD39 on CD4+ CD25high T-reg cells in patients with acute myeloid leukemia to identify its role in immunosuppressive status of AML patients. Methods: Flow cytometric analysis of T-reg cells using CD4 CD25 and CD39 in 60 AML patients and 15 apparently healthy controls with matched age and sex was done. Results: There was a significant difference between cases and controls as regards expression of CD39 on T-helper cells. A highly significant elevation of expression of CD39 has been obtained on T-reg cells in AML patients compared with Controls with increased expression of CD39 on T-reg cells than on helper T cells. Conclusion: CD39 plays a significant role in immunosuppressive status of AML patients particularly with expressing the receptor of α chain of IL-2 (CD25)

Immunological and toxicological effects of bad indoor air to cause dampness and Mold Hypersensitivity Syndrome

Water damage in buildings is a universe problem. Long-lasting or cumulative stay in water damaged buildings is a serious health hazard. Exposure to fungal and bacterial toxins, nanoparticles from dampness microbiota as well as decay products from construction materials together with biocides used for cleaning will first cause irritation of the mucosa and later chronic inflammation with stimulation or inhibition of the compartments of the innate and/or adaptive immunity. Mold-related disease has been called Dampness and Mold Hypersensitive Syndrome (DMHS) because hypersensitivity is the cornerstone feature of the disease. The background of hypersensitivity is both immunologic processes and hyperactivation of sensory receptors, neurogenic inflammation and central sensitisation. Immunologic hypersensitivity can occur either through the production of mold specific IgE-class antibodies, which is rare, or through sensitisation and proliferation of T and B specific lymphocyte clones. Immunological switch to Th2/Th17 arm of adaptive immunity often occurs. DMHS is a systemic and multi-organ disease where involvement of mucosa of pulmonary or gastrointestinal tract is central to the pathology. Symptoms include recurrent infections, chronic rhinosinusitis, swelling of the sinuses, irritation of the eyes and skin, voice problems, chronic non-productive cough, neurological symptoms, joint and muscle symptoms, irritable bowel syndrome and cognitive problems. Underdiagnosed or neglected continuous insidious inflammation may lead to Myalgic Encephalitis/Chronic Fatigue Syndrome (ME/CFS) especially when trigged by new infections or even vaccination. Multiple Chemical Sensitivity (MCS) may also develop, however in the later stages of the disease. Chronic cough is sometimes diagnosed as asthma if the criteria for asthma are met. Non-productive cough may also manifest allergic alveolitis, which is often overlooked. Avoidance of new exposure to dampness microbiota is crucial for recovery. We review the underlying toxicological and immunological mechanisms that are central in the pathology of DMHS.

Meat and Nicotinamide: A Causal Role in Human Evolution, History, and Demographics.

Hunting for meat was a critical step in all animal and human evolution. A key brain-trophic element in meat is vitamin B3 / nicotinamide. The supply of meat and nicotinamide steadily increased from the Cambrian origin of animal predators ratcheting ever larger brains. This culminated in the 3-million-year evolution of Homo sapiens and our overall demographic success. We view human evolution, recent history, and agricultural and demographic transitions in the light of meat and nicotinamide intake. A biochemical and immunological switch is highlighted that affects fertility in the ‘de novo’ tryptophan-to-kynurenine-nicotinamide ‘immune tolerance’ pathway. Longevity relates to nicotinamide adenine dinucleotide consumer pathways. High meat intake correlates with moderate fertility, high intelligence, good health, and longevity with consequent population stability, whereas low meat/high cereal intake (short of starvation) correlates with high fertility, disease, and population booms and busts. Too high a meat intake and fertility falls below replacement levels. Reducing variances in meat consumption might help stabilise population growth and improve human capital.

A switch in regulatory T cells through farm exposure during immune maturation in childhood.

Farm exposure protects against development of allergies early in life. At 4.5 years, protection against asthma by farm-milk exposure was partially mediated by regulatory T cells (Tregs). The aim of this study was to investigate the critical time window of the 'asthma-protective' farm effect via Tregs during childhood immune maturation. Tregs were assessed longitudinally at 4.5 and 6 years in 111 children (56 farm and 55 reference children) from the PASTURE/EFRAIM birth cohort (flow cytometry). Peripheral blood mononuclear cells were cultured unstimulated (U), with phorbol 12-myristate 13-acetate/ionomycin (PI) or lipopolysaccharide (LPS), and stained for Tregs (CD4+ CD25high FOXP3upper20% ). mRNA expression of Treg/Th1/Th2/Th17-associated cell markers was measured ex vivo. Suppressive capacity of Tregs on effector cells and cytokines was assessed. Detailed questionnaires assessing farm exposures and clinical phenotypes from birth until age 6 years were answered by the parents. Treg percentage before and after stimulation and FOXP3mRNA expression ex vivo decreased from age 4.5 to 6 years (P(U,LPS) < 0.001; P(PI) = 0.051; P(FOXP3) < 0.001). High vs low farm-milk and animal-stable exposure was associated with decreased LPS-stimulated Treg percentage at age 6 years (P(LPS) = 0.045). Elevated LPS-stimulated-Treg percentage at age 6 was associated with increased risk of asthma (aOR = 11.29, CI: 0.96-132.28, P = 0.053). Tregs from asthmatics vs nonasthmatics suppressed IFN-γ (P = 0.015) and IL-9 (P = 0.023) less efficiently. mRNA expression of Th1/Th2/Th17-associated cell markers decreased between 4.5 and 6 years (P < 0.001). Tregs at the age of 6 years were decreased with farm exposure and increased within asthmatics, opposite to age 4.5 years. This immunological switch defines a critical 'time window' for Treg-mediated asthma protection via environmental exposure before age 6 years.

The Role of IL-33 in Allergic Disease and Atherosclerosis

IL-33, a new member of the IL-1 cytokine family, may be atheroprotective via induction of a Th1-to-Th2 immunologic switch. However, to date, the role of IL-33 in cardiovascular disease remains unclear. The purpose of this study is to assess the level of IL-33 in atopic patients and its effect on the expression of proteins involved in cholesterol transport.

MMP1, MMP9, and COX2 Expressions in Promonocytes Are Induced by Breast Cancer Cells and Correlate with Collagen Degradation, Transformation-Like Morphological Changes in MCF-10A Acini, and Tumor Aggressiveness

Tumor-associated immune cells often lack immune effector activities, and instead they present protumoral functions. To understand how tumors promote this immunological switch, invasive and noninvasive breast cancer cell (BRC) lines were cocultured with a promonocytic cell line in a Matrigel-based 3D system. We hypothesized that if communication exists between tumor and immune cells, coculturing would result in augmented expression of genes associated with tumor malignancy. Upregulation of proteases MMP1 and MMP9 and inflammatory COX2 genes was found likely in response to soluble factors. Interestingly, changes were more apparent in promonocytes and correlated with the aggressiveness of the BRC line. Increased gene expression was confirmed by collagen degradation assays and immunocytochemistry of prostaglandin 2, a product of COX2 activity. Untransformed MCF-10A cells were then used as a sensor of soluble factors with transformation-like capabilities, finding that acini formed in the presence of supernatants of the highly aggressive BRC/promonocyte cocultures often exhibited total loss of the normal architecture. These data support that tumor cells can modify immune cell gene expression and tumor aggressiveness may importantly reside in this capacity. Modeling interactions in the tumor stroma will allow the identification of genes useful as cancer prognostic markers and therapy targets.

TWEAK/Fn14 pathway: an immunological switch for shaping tissue responses

Our immune system performs the vital function of recognizing and eliminating invading pathogens and malignancies. There is an increasing appreciation that the immune system also actively mediates tissue responses under both physiological and pathological conditions, significantly impacting the inflammatory, fibrogenic, and regenerative components. Likewise, there is a growing understanding of how epithelial, endothelial, and other non-hematopoietic tissue cell types actively contribute to the interplay that shapes tissue responses. While much of the molecular basis underlying the immune regulation of tissue responses remains to be delineated, the tumor necrosis factor (TNF) superfamily ligand/receptor pair of TNF-like weak inducer of apoptosis (TWEAK) and fibroblast growth factor-inducible molecule 14 (Fn14) has now emerged as a key piece of this puzzle. In this review, we first discuss how the usually 'dormant' TWEAK/Fn14 pathway becomes activated specifically in injury and disease contexts. We then summarize how TWEAK-mediated Fn14 signaling triggers a wide range of activities in tissue parenchymal and stromal cells as well as progenitor cells. Finally, we review recent experimental evidence that further supports the functional dichotomy of TWEAK/Fn14 activation in physiological versus pathological tissue responses and its potential therapeutic implications. Whereas transient TWEAK/Fn14 activation promotes productive tissue responses after injury, excessive or persistent TWEAK/Fn14 activation drives pathological tissue responses, leading to progressive damage and degeneration.

Abstract LB-151: Tumor VEGF-C promotes immune suppression and tolerance

Abstract The expression of the vascular endothelial growth factor, VEGF-C, is correlated with tumor invasion and hypothesized to induce metastasis through enhanced lymphangiogenesis and the creation of an “escape route”. However, new evidence suggests that VEGF-C can induce invasion in the absence of obvious tumor lymphangiogenesis, and furthermore, that lymphatic transport may play a role in modulating immunity. Still however, the role of the lymphatics as players in anti-tumor immunity and tumor invasion remains unexplored. Here we present a new model for VEGF-C induced tumor-invasion in which VEGF-C and lymphatic endothelial cells play a direct role in the suppression of anti-tumor immunity. Using a B16 F10 mouse melanoma that overexpresses VEGF-C, we demonstrated that VEGF-C induces the expression of the lymphoid homing cytokine, CCL21, within the stroma of the tumor and drives lymphocyte trafficking, fluid drainage and metastasis to the sentinel draining lymph node. Within the tumor stroma VEGF-C recruited a more regulatory immune cell infiltrate including increased regulatory T cells (CD25+FoxP3+) and M2 macrophages (CD11b+CD80-CD206+) and decreased antigen specific cytotoxic T cells (CD8+Trp2+). To test the ability of this mediated VEGF-C response to overcome host immunity we engineered a B16 F10 line to express ovalbumin (OVA) as a model tumor antigen. When we preimmunized the mice against OVA we observed that VEGF-C provided protection against vaccine (OVA/LPS) induced anti-tumor immunity. Growth of OVA bearing tumors was inhibited with vaccination and correlated with an increase in CD8+ antigen specific cytotoxic T cells. However, neither the growth nor the infiltration of cytotoxic T cells was affected by vaccination when the tumors also overexpressing VEGF-C. Additionally, to determine the fate of antigen specific CD8+ we adoptively transferred OT-I T cells by tail vein injection and observed their homing to the draining lymph nodes and tumor. In these microenvironments, when exposed to VEGF-C, adoptively transferred cells lost function over time as shown by the detection of Annexin V and decreased IFNγ expression. These results suggest that the expression of VEGF-C by a primary tumor not only promotes metastasis through the expansion of the lymphatic network but also through an immunological switch within the tumor and draining lymph node. We therefore present one of the first studies to identify an active, rather than passive, role for the lymphangiogenic growth factor, VEGF-C, and local lymphatic endothelial cells in the regulation of tumor immunity. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-151. doi:10.1158/1538-7445.AM2011-LB-151

Superior Efficacy of Tumor Cell Vaccines Grown in Physiologic Oxygen

Atmospheric oxygen (∼20% O(2)) has been the universal condition employed to culture tumor cells used as vaccine antigen. We tested the hypothesis that reducing oxygen tension would increase the efficacy of tumor cell lysate vaccines. GL261 glioma cells and EMT6 breast carcinoma cells were grown in 5% or 20% O(2). Syngeneic tumor-bearing mice were vaccinated with these tumor cell lysates mixed with CpG oligodeoxynucleotides as an adjuvant. Tumor infiltrating T cells and apoptotic GL261 cells were quantified by immunohistochemistry. Tumor-reactive immunoglobulin was detected by Western blot. Ovalbumin and gp100-derived peptides were mixed with GL261 lysates as marker antigens to detect changes in presentation of exogenous antigen on MHC class I in vitro, and in vivo following adoptive transfer of gp100-specific CD8(+) T cells. Mice bearing orthotopic glioma and breast carcinoma survived significantly longer when vaccinated with 5% O(2) lysates. Antigen-specific CTL activation was significantly enhanced following stimulation with lysates derived from GL261 cells grown in 5% O(2) versus 20% O(2) through a mechanism that involved enhanced cross-presentation of exogenous antigen on MHC I. Vaccination with 5% O(2) GL261 cell lysates caused a significant increase in CTL proliferation, tumoricidal function, and trafficking into brain tumor sites, whereas 20% O(2) lysate vaccines predominantly evoked an antibody response. Tissue culture oxygen functions as an "immunologic switch" by dictating the cellular and humoral immune responses elicited by tumor cell lysates. These results have profound implications for cancer vaccines that utilize tumor cells as the source of antigen.

Is vitamin E a safe prophylaxis for preeclampsia?

The prophylactic use of vitamins E and C for the prevention of preeclampsia is currently being evaluated in multiple clinical trials in Canada, Mexico, the United Kingdom, the United States, and other developing countries. In addition to its antioxidant capacity, exogenous vitamin E may prevent an immunologic switch (Th1 to Th2) that is vital for early-to late transition in normal pregnancies. Moreover, vitamin E could be a potential interferon-gamma (IFN-gamma) mimic facilitating persistent proinflammatory reactions at the fetal-maternal interface. These untoward effects of dietary intake of vitamin E may be more pronounced in those treated cases that fail to develop preeclampsia. A critical test of this hypothesis would be to establish whether, under variable O2 tension, vitamin E is capable of affecting cytokine signaling in placental trophoblasts and maternal immune effector cells, both in early and late human pregnancies.

The Cooperation between Two CD4 T Cells Induces Tumor Protective Immunity in MUC.1 Transgenic Mice

Immunity and tumor protection in mice transgenic for human MUC.1, a glycoprotein expressed in the majority of cancers of epithelial origin in humans, were induced by vaccination with B lymphocytes genetically programmed to activate MUC.1-specific CD4 T cells. Their activation required a functional cooperation between two Th cells, one specific for a self (MUC.1) and the other for a nonself T cell determinant. The immunological switch provided by Th-Th cooperation was sufficient to induce MUC.1-specific CD4 and CD8 T cell responses in MUC.1-transgenic mice, and protect them permanently from tumor growth. CD4 T cells specific for MUC.1 lacked cytolytic function, but produced IFN-gamma upon restimulation with Ag. We conclude that immunity against tumor self-Ags and tumor protection can be regulated exploiting an inherent property of the immune system.