Hans Dooms

National Jewish Health · Department of Immunology

Signal transducer and activator of transcription 5 (STAT5) plays an important role in regulating gene expression in response to cytokines of the common (γc) chain family. In this capacity, STAT5 promotes CD8⁺ effector and memory T cell survival and regulatory T cell development. However, its function in conventional CD4⁺ T cells is less clear. In t...

Despite many decades of investigation uncovering the autoimmune mechanisms underlying Type 1 Diabetes (T1D), translating these findings into effective therapeutics has proven extremely challenging. T1D is caused by autoreactive T cells that become inappropriately activated and kill the β cells in the pancreas, resulting in insulin insufficiency and...

Community-acquired pneumonia is a widespread disease with significant morbidity and mortality. Alveolar macrophages are tissue-resident lung cells that play a crucial role in innate immunity against bacteria that cause pneumonia. We hypothesized that alveolar macrophages display adaptive characteristics after resolution of bacterial pneumonia. We s...

Autoantigen-specific methods to prevent and treat Type 1 Diabetes (T1D) carry high hopes to permanently cure this disease, but have largely failed in clinical trials. One suggested approach to increase the efficacy of islet antigen-specific vaccination is to combine it with a modulator of the T cell response, with the goal of reducing effector diff...

Representative gating strategy to identify antigen-specific CD4+ T cells with BDC2.5 pMHC II/PE tetramers. (PDF)

Systemic sclerosis (SSc) is an autoimmune connective tissue disorder associated with aberrant fibrosis of the skin and internal organs that can lead to organ failure and death in patients. With few treatment options many patients succumb to fibrosis of the lungs or kidneys, or due to vascular damage culminating in pulmonary disease; the 50 percent...

Objective: Immune dysfunction is an important component of the disease process underlying Systemic Sclerosis (SSc), but the mechanisms contributing to altered immune cell function in SSc remain poorly defined. Here, we measured the expression and function of the co-inhibitory receptors (co-IRs) PD-1, TIGIT, TIM-3, and LAG-3 in lymphocyte subsets f...

Triggers of the autoimmune response that leads to type 1 diabetes (T1D) remain poorly understood. A possibility is that parallel changes in both T cells and target cells provoke autoimmune attack. We previously documented greater Ca²⁺ transients in fibroblasts from T1D subjects than non-T1D after exposure to fatty acids (FA) and tumor necrosis fact...

T1D donor treatment information. Information regarding the age, sex and treatment at time of donation of all T1D donors (fibroblasts and PBMCs). (TIF)

Inhibitory Receptors (IRs) such as PD-1, TIM-3, CD160, and TIGIT are upregulated during activated, exhausted, and pathological immune cell states. How the combinational expression of multiple IRs on individual cells tracks with functional status and/or fate is largely unknown. Due to paucity of human samples, large panels for immune cell characteri...

As children age, they become less susceptible to the diverse microbes causing pneumonia. These microbes are pathobionts that infect the respiratory tract multiple times during childhood, generating immunological memory. To elucidate mechanisms of such naturally acquired immune protection against pneumonia, we modeled a relevant immunological histor...

Inhibitory Receptors (IRs) such as PD-1, TIM-3, CD160, and TIGIT are upregulated during activated, exhausted, and pathological immune cell states. How the combinational expression of multiple IRs on individual cells tracks with functional status and/or fate is largely unknown. Due to paucity of human samples, large panels for immune cell characteri...

Inhibitory Receptors (IRs) such as PD-1, TIM-3, CD160, and TIGIT are upregulated during activated, exhausted, and pathological immune cell states. How the combinational expression of multiple IRs on individual cells tracks with functional status and/or fate is largely unknown. Due to paucity of human samples, large panels for immune cell characteri...

Systemic sclerosis (SSc) is an autoimmune connective tissue disorder associated with aberrant fibrosis of the skin and internal organs that can lead to organ failure and death in patients. With few treatment options many patients succumb to fibrosis of the lungs or kidneys, or due to vascular damage culminating in pulmonary disease; the 50 percent...

Background Type 1 diabetes is an autoimmune disease caused by T cell-mediated destruction of the insulin-producing ?-cells in the pancreas. Therefore, approaches that effectively halt the pathogenic T cell response are predicted to have preventive or therapeutic benefit for type 1 diabetes patients. We previously demonstrated that long-term blockin...

Numerous studies show that mitochondrial energy generation determines the effectiveness of immune responses. Furthermore, changes in mitochondrial function may regulate lymphocyte function in inflammatory diseases like type 2 diabetes. Analysis of lymphocyte mitochondrial function has been facilitated by introduction of 96-well format extracellular...

Background. The phenotypic profiles of both peripheral blood and tissue-resident immune cells have been linked to the health status of individuals with infectious and autoimmune diseases, as well as cancer. In light of the promising clinical trial results of agents that block the Inhibitory Receptor (IR) Programmed Death 1 (PD-1) axis, novel flow c...

Interleukin-7 (IL-7) is a critical survival factor for lymphocytes and recent studies suggest targeting the IL-7/IL-7Rα pathway holds promise for the treatment of autoimmune diseases. Several lines of evidence, genetic as well as functional, indicate an important role for this cytokine in autoimmune inflammation: polymorphisms in the IL-7Rα have be...

Natural regulatory T cells (nTreg) play a central role in the induction and maintenance of immunological tolerance. Experimental transplant models and recent clinical trials demonstrate that nTreg can control alloreactivity. To upgrade Treg-based cell therapies to a selective suppression of undesired immune reactions, only the transfer of Ag-specif...

Due to its critical role in NK cell differentiation and CD8(+) T cell homeostasis, the importance of IL-15 is more firmly established for cytolytic effectors of the immune system than for CD4(+) T cells. The increased levels of IL-15 found in several CD4(+) T cell-driven (auto-) immune diseases prompted us to examine how IL-15 influences murine CD4...

To protect the organism against autoimmunity, self-reactive effector/memory T cells (T(E/M)) are controlled by cell-intrinsic and -extrinsic regulatory mechanisms. However, how some T(E/M) cells escape regulation and cause autoimmune disease is currently not understood. Here we show that blocking IL-7 receptor-α (IL-7Rα) with monoclonal antibodies...

Regulation of the magnitude and quality of immune responses is dependent on the integration of multiple signals which typically operate through positive and negative feedback loops. Cytokines that promote or limit T cell expansion and differentiation are often both present in the complex lymphoid environment where antigen-initiated T cell responses...

An important challenge in the therapy of immune-mediated inflammatory diseases is to control established disease, largely because autoreactive memory T lymphocytes are difficult to suppress or eliminate. Memory T cells depend on interleukin-7 (IL-7) for their generation and maintenance and genomic studies have associated the cytokine’s receptor, IL...

IL-2 controls the survival of regulatory T cells (Tregs), but it is unclear whether IL-2 also directly affects Treg suppressive capacity in vivo. We have found that eliminating Bim-dependent apoptosis in IL-2- and CD25-deficient mice restored Treg numbers but failed to cure their lethal autoimmune disease, demonstrating that IL-2-dependent survival...

IL-2 was discovered as a T-cell growth factor that promoted T-cell-dependent immune responses; however, more recent studies suggest that the essential role of IL-2 is to maintain functional Treg and thus control immune responses. These results are leading to new ideas about the potential of IL-2 as a therapeutic strategy in autoimmune diseases. In...

An early reaction of CD4(+) T lymphocytes to Ag is the production of cytokines, notably IL-2. To detect cytokine-dependent responses, naive Ag-specific T cells were stimulated in vivo and the presence of phosphorylated STAT5 molecules was used to identify the cell populations responding to IL-2. Within hours of T cell priming, IL-2-dependent STAT5...

Interleukin-2 (IL-2) has multiple, sometimes opposing, functions during an inflammatory response. It is a potent inducer of T-cell proliferation and T-helper 1 (Th1) and Th2 effector T-cell differentiation and provides T cells with a long-lasting competitive advantage resulting in the optimal survival and function of memory cells. In a regulatory r...

Although it is established that failure of regulatory mechanisms underlies many autoimmune diseases, the stimuli that activate autoreactive lymphocytes remain poorly understood. Defining these stimuli will lead to therapeutic strategies for autoimmune diseases. IL-2-deficient mice develop spontaneous autoimmunity, because of a deficiency of regulat...

The common gamma chain cytokines interleukin (IL)-2 and IL-7 are important regulators of T cell homeostasis. Although IL-2 is implicated in the acute phase of the T cell response, IL-7 is important for memory T cell survival. We asked whether regulated responsiveness to these growth factors is determined by temporal expression of the cytokine-speci...

During T-cell priming, cytokines and costimulatory molecules provide important signals that determine the magnitude and quality of the response. Although the functions of defined cytokines and costimulators in the primary T-cell response are well characterized, much less is known about how these factors contribute to memory T-cell development and s...

The acquisition of long-term survival potential by activated T lymphocytes is essential to ensure the successful development of a memory population in the competitive environment of the lymphoid system. The factors that grant competitiveness for survival to primed T cells are poorly defined. We examined the role of IL-2 signals during priming of CD...

The failure of CD25+ regulatory T cells (Tregs) to proliferate after T cell receptor (TCR) stimulation in vitro has lead to their classification as naturally anergic. Here we use Tregs expressing a transgenic TCR to show that despite anergy in vitro, Tregs proliferate in response to immunization in vivo. Tregs also proliferate and accumulate locall...

TCR/CD3 aggregation by injection of anti-CD3 Ab produces T cell activation, release of cytokines such as IFN-gamma, and apoptosis in the cortical region of the thymus. We show that anti-CD3 Ab induces IL-15 mRNA in spleens of wild-type but not IFN-gamma receptor-knock-out (IFN-gammaR KO) mice. The loss of IL-15 mRNA induction in IFN-gammaR KO mice...

The existence of two distinct lineages of THI cell may explain the relationship between activated effector THI cell and long-term THI memory cells.

Clonal deletion and anergy are 2 mechanisms used by the immune system to establish peripheral tolerance. In vitro, these mechanisms are induced in T lymphocytes by triggering the T-cell receptor (signal 1) in the absence of costimulation (signal 2). T-cell clones have been shown either to become anergic or to die in response to signal 1 alone; yet...

Clonal deletion and anergy are 2 mechanisms used by the immune system to establish peripheral tolerance. In vitro, these mechanisms are induced in T lymphocytes by triggering the T-cell receptor (signal 1) in the absence of costimulation (signal 2). T-cell clones have been shown either to become anergic or to die in response to signal 1 alone; yet...

Time kinetics of phosphatidyl serine (PS) exposure were compared to other apoptotic parameters following different apoptotic stimuli. Our data indicate that anti-Fas treatment of L929sAhFas cells results in rapid exposure of PS, which precedes decrease in mitochondrial transmembrane potential (DeltaPsi(m)) and release of cytochrome c, indicating th...

In addition to eugenetic changes, cancerous cells exhibit extensive modifications in the expression levels of a variety of genes. The phenotypic switch observed after inoculation of T lymphoma cells into syngenic mice illustrates the active participation of tumoral environment in the induction of an aberrant gene expression pattern. To further subs...

Progression to malignancy of transformed cells involves complex genetic alterations and aberrant gene expression patterns. While aberrant gene expression is often caused by alterations in individual genes, the contribution of the tumoral environment to the triggering of this gene expression is less well established. The stable but heterogeneous exp...

IL-15 shows functional redundancy with IL-2 due to its usage of the beta and gamma c subunit of the IL-2R. Yet, the requirement of IL-15 for an IL-15R alpha chain for high affinity interaction and the separate cellular sources of IL-2 and IL-15 suggest divergent activities for both cytokines. We compared the growth-inducing and proapoptotic or anti...

Differentiation of naive CD4+ T cells (Th0) into Th1 or Th2 cells determines whether antigen will raise a cellular or a humoral immune response. The maturation pathway chosen by the Th0 cell is often decisive for the outcome of disease and depends among others on the (co-)stimulatory attributes of the APC and the nature and abundance of cytokines p...