Sumit Sen Santara

Bio: Sumit Sen Santara is an academic researcher from Boston Children's Hospital. The author has contributed to research in topics: Immune system & Globin. The author has an hindex of 8, co-authored 13 publications receiving 214 citations. Previous affiliations of Sumit Sen Santara include Indian Institute of Chemical Biology & Council of Scientific and Industrial Research.

Cytotoxic CD8+ T cells recognize and kill Plasmodium vivax-infected reticulocytes.

Abstract: Plasmodium vivax causes approximately 100 million clinical malaria cases yearly1,2 The basis of protective immunity is poorly understood and thought to be mediated by antibodies3,4 Cytotoxic CD8+ T cells protect against other intracellular parasites by detecting parasite peptides presented by human leukocyte antigen class I on host cells Cytotoxic CD8+ T cells kill parasite-infected mammalian cells and intracellular parasites by releasing their cytotoxic granules5,6 Perforin delivers the antimicrobial peptide granulysin and death-inducing granzymes into the host cell, and granulysin then delivers granzymes into the parasite Cytotoxic CD8+ T cells were thought to have no role against Plasmodium spp blood stages because red blood cells generally do not express human leukocyte antigen class I7 However, P vivax infects reticulocytes that retain the protein translation machinery Here we show that P vivax–infected reticulocytes express human leukocyte antigen class I Infected patient circulating CD8+ T cells highly express cytotoxic proteins and recognize and form immunological synapses with P vivax–infected reticulocytes in a human leukocyte antigen–dependent manner, releasing their cytotoxic granules to kill both host cell and intracellular parasite, preventing reinvasion P vivax–infected reticulocytes and parasite killing is perforin independent, but depends on granulysin, which generally efficiently forms pores only in microbial membranes8 We find that P vivax depletes cholesterol from the P vivax–infected reticulocyte cell membrane, rendering it granulysin-susceptible This unexpected T cell defense might be mobilized to improve P vivax vaccine efficacy T cells kill blood-stage Plasmodium vivax, providing a rationale for the development of a T cell vaccine against this parasite

γδ T cells suppress Plasmodium falciparum blood-stage infection by direct killing and phagocytosis.

Abstract: Activated Vγ9Vδ2 (γδ2) T lymphocytes that sense parasite-produced phosphoantigens are expanded in Plasmodium falciparum–infected patients. Although previous studies suggested that γδ2 T cells help control erythrocytic malaria, whether γδ2 T cells recognize infected red blood cells (iRBCs) was uncertain. Here we show that iRBCs stained for the phosphoantigen sensor butyrophilin 3A1 (BTN3A1). γδ2 T cells formed immune synapses and lysed iRBCs in a contact, phosphoantigen, BTN3A1 and degranulation-dependent manner, killing intracellular parasites. Granulysin released into the synapse lysed iRBCs and delivered death-inducing granzymes to the parasite. All intra-erythrocytic parasites were susceptible, but schizonts were most sensitive. A second protective γδ2 T cell mechanism was identified. In the presence of patient serum, γδ2 T cells phagocytosed and degraded opsonized iRBCs in a CD16-dependent manner, decreasing parasite multiplication. Thus, γδ2 T cells have two ways to control blood-stage malaria–γδ T cell antigen receptor (TCR)-mediated degranulation and phagocytosis of antibody-coated iRBCs. Junqueira et al. show that human γδ T cells control erythrocytic Plasmodium falciparum infection by multiple mechanisms: antibody-dependent phagocytosis, cytotoxic-granule-mediated erythrocyte lysis and direct parasite killing.

Globin-coupled heme containing oxygen sensor soluble adenylate cyclase in Leishmania prevents cell death during hypoxia

Abstract: Globin and adenylate cyclase play individually numerous crucial roles in eukaryotic organisms. Comparison of the amino acid sequences of globins and adenylate cyclase from prokaryotic to eukaryotic organisms suggests that they share an early common ancestor, even though these proteins execute different functions in these two kingdoms. The latest studies of biological signaling molecules in both prokaryotic and eukaryotic organisms have discovered a new class of heme-containing proteins that act as sensors. The protein of the globin family is still unknown in the trypanosomatid parasites, Trypanosome and Leishmania. In addition, globin-coupled heme containing adenylate cyclase is undescribed in the literature. Here we report a globin-coupled heme containing adenylate cyclase (HemAC-Lm) in the unicellular eukaryotic organism Leishmania. The protein exhibits spectral properties similar to neuroglobin and cytoglobin. Localization studies and activity measurements demonstrate that the protein is present in cytosol and oxygen directly stimulates adenylate cyclase activity in vivo and in vitro. Gene knockdown and overexpression studies suggest that O2-dependent cAMP signaling via protein kinase A plays a fundamental role in cell survival through suppression of oxidative stress under hypoxia. In addition, the enzyme-dependent cAMP generation shows a stimulatory as well as inhibitory role in cell proliferation of Leishmania promastigotes during normoxia. Our work begins to clarify how O2-dependent cAMP generation by adenylate cyclase is likely to function in cellular adaptability under various O2 tensions.

Natural Killer Cells: Development, Maturation, and Clinical Utilization

Abstract: Natural killer cells are the predominant innate lymphocyte subsets that mediate anti-tumor and anti-viral responses, and therefore possess promising clinical utilization. NK cells do not express polymorphic clonotypic receptors and utilize inhibitory receptors (KIR and Ly49) to develop, mature, and recognize ‘self’ from ‘non-self’. The essential roles of common gamma cytokines such as IL-2, IL-7, and IL-15 in the commitment and development of NK cells are well-established. However, the critical functions of proinflammatory cytokines IL-12, IL-18, IL-27, and IL-35 in the transcriptional-priming of NK cells are only starting to emerge. Recent studies have highlighted multiple shared characteristics between NK cells the adaptive immune lymphocytes. NK cells utilize unique signaling pathways that offer exclusive ways to genetically manipulate to improve their effector functions. Here, we summarize the recent advances made in the understanding of how NK cells develop, mature, and their potential translational use in the clinic.

Structure and function of the immune system in the spleen

Abstract: The spleen is the largest secondary lymphoid organ in the body and, as such, hosts a wide range of immunologic functions alongside its roles in hematopoiesis and red blood cell clearance. The physical organization of the spleen allows it to filter blood of pathogens and abnormal cells and facilitate low-probability interactions between antigen-presenting cells (APCs) and cognate lymphocytes. APCs specific to the spleen regulate the T and B cell response to these antigenic targets in the blood. This review will focus on cell types, cell organization, and immunologic functions specific to the spleen and how these affect initiation of adaptive immunity to systemic blood-borne antigens. Potential differences in structure and function between mouse and human spleen will also be discussed.

An early history of T cell-mediated cytotoxicity

Abstract: After 60 years of intense fundamental research into T cell-mediated cytotoxicity, we have gained a detailed knowledge of the cells involved, specific recognition mechanisms and post-recognition perforin-granzyme-based and FAS-based molecular mechanisms. What could not be anticipated at the outset was how discovery of the mechanisms regulating the activation and function of cytotoxic T cells would lead to new developments in cancer immunotherapy. Given the profound recent interest in therapeutic manipulation of cytotoxic T cell responses, it is an opportune time to look back on the early history of the field. This Timeline describes how the early findings occurred and eventually led to current therapeutic applications.

Challenges and strategies for developing efficacious and long-lasting malaria vaccines

Abstract: Although there has been major recent progress in malaria vaccine development, substantial challenges remain for achieving highly efficacious and durable vaccines against Plasmodium falciparum and Plasmodium vivax malaria. Greater knowledge of mechanisms and key targets of immunity are needed to accomplish this goal, together with new strategies for generating potent, long-lasting, functional immunity against multiple antigens. Implementation considerations in endemic areas will ultimately affect vaccine effectiveness, so innovations to simplify and enhance delivery are also needed. Whereas challenges remain, recent exciting progress and emerging knowledge promise hope for the future of malaria vaccines.

How to master the host immune system? Leishmania parasites have the solutions!

Abstract: Infection by protozoan parasites of the genus Leishmania results in the development of leishmaniasis, an increasingly prevalent group of diseases affecting over 12 million people worldwide. Leishmaniasis can have very different outcomes ranging from cutaneous lesions, mucosal lesions to visceralization depending on the species of the infecting parasite and on the immune response developed by the host. As an obligate intracellular parasite, residing within macrophages, Leishmania evolved in strict contact with the host immune system, developing different mechanisms to evade or modulate the immune response. Various types of immune responses are observed during different Leishmania spp. infections, resulting in parasite clearance but also contributing to the pathogenesis, thus increasing the complexity of the course of the disease. Interestingly, depending on the type of leishmaniasis developed, opposite treatment strategies, which either boost or inhibit the inflammatory response, have shown efficacy. In this review, we summarize the contribution of different immune cell types to the development of the anti-leishmanial immune response and the parasite strategies to evade and modulate host immunity. Further, we discuss the involvement of co-infecting pathogens in the determination of the outcome of leishmaniasis and on the effectiveness of treatment and the implication of the immune response for treatment and vaccine development.