Research Area: Immunology

Alison E. Ringel

Education

  • PhD, 2015, Johns Hopkins University School of Medicine
  • BA, 2009, Molecular Biology & Biochemistry/Physics, Wesleyan University

Research Summary

We investigate crosstalk between CD8+ T cells and their environment at a molecular level, by dissecting the biological and metabolic programs engaged under conditions of stress. Using an array of approaches to model and perturb the local microenvironment, our research aims to reveal both the adaptive molecular changes as well as intrinsic vulnerabilities in T cells that arise within the tumor niche. Our goal is to understand how disease states remodel the fundamental mechanisms that regulate immune cell function and contribute to pathogenesis.

Awards

  • Forbeck Scholar, 2021
Harikesh S. Wong

Education

  • PhD, 2016, University of Toronto
  • BSc, 2010, Biochemistry, McMaster University

Research Summary

The immune system mounts destructive responses to protect the host from threats, including pathogens and tumors. However, a trade-off emerges: if immune responses cause too much damage, they can compromise host tissue function. Conversely, if they fail to generate sufficient damage, the host may succumb to a given threat. How is the optimal balance achieved? The Wong lab investigates how cells communicate with one another and their surrounding tissue environment to accurately control the magnitude of immune responses, both in time and space. To this end, we combine the tools of immunology with interdisciplinary methods—including high-resolution fluorescence microscopy, computational approaches, and gene manipulations—to resolve, model, and perturb the control of immune responses in intact tissues. Ultimately, we aim to understand how subtle shifts in control can lead to widely divergent host outcomes, including the successful elimination of threats, tolerance, autoimmunity, chronic infection, and cancer.

Hernandez Moura Silva

Education

  • PhD, 2011, University of São Paulo Heart Institute
  • MSc, Molecular Biology, 2008, University of Brasilia
  • BS, 2005, Biology, University of Brasilia

Research Summary

By utilizing an innovative and intersectional approach, our lab main goal is to reveal fundamental immune-related pathways that modulate organ and tissue physiology. Our work will help to develop new strategies to tune these molecular pathways in health and disease, leading to the development of much-needed therapeutic approaches for human diseases.

Awards

  • CAPES Thesis Award – Brazil, 2012
Vaccine Booster

Biologist Jianzhu Chen works to enhance immune response

Mark Wolverton | Spectrum
November 16, 2020

Jianzhu Chen, professor of biology and a member of the Koch Institute for Integrative Cancer Research at MIT, is pursuing a different strategy from most of his colleagues working on SARS-CoV-2, the virus that causes Covid-19. “We focus on the immune system and fundamental mechanisms as well as their application in cancer immunotherapy, vaccine development, and metabolic diseases,” he explains. Rather than trying to develop a specific vaccine, Chen is pursuing vaccine platform technologies that can be used to enhance any vaccine.

This effort is built on Chen’s previous work on dengue fever, a severe tropical disease transmitted by mosquitos. “We have been working to improve a vaccine against dengue virus infection,” he says, “which has this phenomenon called antibody-dependent enhancement,” in which “non-neutralizing” antibodies bind to the virus but do not destroy it. The immune system’s pathogen-eating macrophages then consume these virus-antibody complexes and become infected themselves, making a subsequent infection worse.

Chen’s team has identified vaccine adjuvants, or enhancing agents, that can increase neutralizing (that is, effective) antibodies while reducing non-neutralizing antibody response in mice and nonhuman primates. The team is confident that using a similar strategy against Covid-19 would improve any vaccine’s effectiveness.

Addressing cytokine storm

Chen is also focusing on the dangerous hyperinflammatory response seen in Covid-19: the cytokine storm that can result when the immune system overreacts to infection.

“We have been working on macrophage biology for quite some time,” Chen says. “SARS-CoV-2 infection is a hyperinflammatory response, and macrophages probably play a critical role in that response.”

“We have identified many compounds, including FDA-approved drugs, bioactive compounds, and natural products that can modulate macrophage activity to become anti-inflammatory,” he says. Such macrophage modulation would likely be used in conjunction with other treatments as a therapeutic strategy for already-infected patients.

A promising result from either research project could be used along with a Covid-19 vaccine to enhance immune response while preventing or reducing the severity of any possible reinfection. But it’s too early to tell what might happen. “We don’t have a vaccine yet,” Chen notes. “It’s not clear when we’ll have one. Even when we have one, it’s not clear how well it will work. It could be 95% protection; it could be 50%. Some of them may not confer much protection at all. But even 50% or 60% is a significant number of people.”

Another challenge, Chen acknowledges, is that medical research must move from theory to lab and ultimately into the real world. Vaccines can be designed and modeled on computers but eventually “we have to test them to see if they work as we expect,” he says. “You have to immunize mice or some other animals and then challenge them with SARS-CoV-2 to see whether the vaccine protects the animals from infection or dramatically minimize disease symptoms. These kinds of studies can’t be modeled computationally.”

Chen also hopes that his particular contributions will have benefits beyond the pandemic. “We’re aiming to develop a vaccine platform prototyped on SARS-CoV-2 that can be used for the development of many other vaccines as well, using the most appropriate technologies.” If that happens, science will have dug at least one substantial jewel out of the depths of an unprecedented public health crisis.

Type 1 diabetes from a beta cell’s perspective
Eva Frederick | Whitehead Institute
September 24, 2020

Type 1 diabetes is an autoimmune disease that occurs when T-cells in the immune system attack the body’s own insulin-producing cells, called beta cells, in the pancreas. Usually diagnosed in children and young adults, type 1 diabetes accounts for around five percent of all diabetes cases.

The underlying biology of type 1 diabetes is tricky to study for a number of reasons. For one thing, by the time a person begins to show symptoms, their T-cells have already been destroying beta cells for a long period — months or even years. Also, the initial trigger for the disease is often unclear; a number of beta cell proteins can set off the immune response.

In a study published Sept. 22 in Cell Reports Medicine, researchers in the lab of Whitehead Institute Founding Member Rudolf Jaenisch demonstrate a new experimental system for more precisely studying the mechanisms of type 1 diabetes, focusing on how a person’s beta cells respond to an attack from their own immune system. In doing so, they reveal features of the disease that could be targets for future therapeutics.

“Here our question was, let’s say the T cells get activated; what happens next from the perspective of beta cells? Could we find some potential intervention opportunities?” said Haiting Ma, a postdoctoral associate in Jaenisch’s lab and the first author of the study.

Ma, working with Jaenisch, also a professor of biology at MIT, and Jacob Jeppesen, Novo Nordisk’s Head of Diabetes and Metabolism Biology, took a synthetic biology approach to achieve this goal.

The researchers engineered a system by inducing human pluripotent stem cells to differentiate into functional pancreatic beta cells, and added a model antigen called CD19 to these cells using CRISPR techniques. They established that these cells functioned as insulin-producing beta cells by implanting them in diabetic mice; upon receiving the cells, the mice experienced an improvement in glucose levels.

They then replicated the autoimmune components of the disease using engineered immune cells called CAR-T cells. CAR-T cells are T-cells tailor-made to attack a certain type of cell; for example, they can be targeted to tumor cells to treat certain types of cancer. For the diabetes model, the researchers engineered the cells to contain receptors for the model antigen CD19.

When the researchers cocultured the synthetic beta cells and CAR-T cells, they found the system worked well to mimic a simplified version of type 1 diabetes: the CAR-T cells attacked the beta cells and caused them to enter the process of cell death. The researchers were also able to implement the strategy in humanized mice.

Using their new experimental system, the researchers were able to identify some interesting factors involved in the beta cells’ response to diabetic conditions. For one thing, they found that the beta cells cranked up production of protective mechanisms such as the protein PDL1. PDL1 is a protein found on non-harmful cells in the body that, in normal circumstances, prevents the immune system from attacking them.

Changes in PDL1 levels had been associated with type 1 diabetes in previous studies. Now, Ma wondered if it was possible to rescue the beta cells from the immune onslaught by inducing the expression of even more of the helpful protein. “We found that we can help beta cells by giving them a higher expression of PDL1,” he said. “When we do this, they can do better in the model.” If validated in human cells, increasing expression of PDL1 could be evaluated as a potential therapeutic method, Ma said.

Another finding concerned the way the cells died after T-cell attack. Ma found that the genes that were being upregulated as the beta cells were under attack were associated not with the usual form of cell death, apoptosis, but with a more inflammatory and violent kind of cell death called pyroptosis.

“The interesting thing about pyroptosis is that it causes the cells to release their contents,” Ma said. “This is in contrast to apoptosis, which is considered to be the main mechanism for autoimmune response. We think that pyroptosis could play a role in propelling this autoimmune reaction, because the contents from beta cells include multiple potential antigens. If these are released, they can be picked out by antigen presenting cells and start to crank up this autoimmunity.”

The process of pyroptosis in the context of beta cell autoimmunity could be linked to ER stress in beta cells, a highly secretory cell type. Indeed, an ER stress inducing chemical increased the marker of pyroptosis.

If researchers could find a way to inhibit the process of pyroptosis safely in humans, it could potentially lessen the severity of the autoimmune reaction that is the hallmark of type 1 diabetes. Pyroptosis is mediated by a protein called caspase-4, which can be inhibited in the lab. “If that can be validated in patient beta cells, that could indicate that modulating caspases could also be [a therapeutic mechanism],” Ma said.

Going forward, Ma and Jaenisch plan to investigate the immune mechanisms underlying autoimmunity in humans by using induced pluripotent stem cells from patients with type 1 diabetes. “These cells could be differentiated into immune cells such as T, B, macrophage, and dendritic cells, and we can investigate how they interact with beta cells,” Ma said.

They also plan to keep improving their new experimental system. “This system provides a very robust and tractable synthetic immune response that we can use to study type 1 diabetes,” said Jaenisch. “In the future it could be used to study other autoimmune diseases.”

This study was supported by a generous gift from Liliana and Hillel Bachrach, a collaborative research agreement from Novo Nordisk, and NIH grant 1R01-NS088538 (to R.J.).

***

Written by Eva Frederick

***

Citation:

Ma, H., Jeppesen, J, and Jaenisch, R. “Human T-cells expressing a CD19 CAR-T receptor provide insights into mechanisms of human CD19 positive cell destruction.” Cell Reports Medicine. Sept 22. https://doi.org/10.1016/j.xcrm.2020.100097

A Wide Net to Trap Cancer

Stefani Spranger is exploring multiple avenues for the next immunotherapy breakthrough

Pamela Ferdinand | Spectrum
March 12, 2019

A YOUNG LAB AT THE FOREFRONT OF IMMUNOTHERAPY DISCOVERIES is an exciting yet challenging place to be. MIT faculty member Stefani Spranger, an expert in cancer biology and immunology, understands that better than most people.

Spranger knows that new labs such as hers, which opened in July 2017 at the Koch Institute for Integrative Cancer Research at MIT, face distinct advantages and disadvantages when it comes to making their mark. While younger labs typically have startup grants, they lack the long-term funding, track record, and name recognition of established researchers; on the other hand, new labs tend to have smaller, close-knit teams open to tackling a wider array of investigative avenues to see what works, what doesn’t work, and where promise lies.

That’s when the funds and recognition of an endowed professorship can make a big difference, says Spranger, an assistant professor of biology who last year was named the Howard S. (1953) and Linda B. Stern Career Development Professor. “Not everything will work, so being able to test multiple approaches accelerates discovery and success,” she says.

Spranger is working to understand the mechanisms underlying interactions between cancer and the immune system—and ultimately, to find ways to activate immune cells to recognize and fight the disease. Cancer immunotherapies (the field in which this past year’s Nobel Prize in Physiology or Medicine was awarded) have revolutionized cancer treatment, leading to a new class of drugs called checkpoint inhibitors and resulting in lasting remissions, albeit for a very limited number of cancer patients. According to Spranger, there won’t be a single therapy, one-size-fits-all solution, but targeted treatments for cancers depending on their characteristics.

To discover new treatments, Spranger’s lab casts a wide net, asking big-picture questions about what influences anti-tumor immune response and disease outcome while also zooming in to investigate, for instance, specifically how cancer-killing T cells are excluded from tumors. In 2015, as a University of Chicago postdoc, Spranger made the novel discovery that malignant melanoma tumors with high beta-catenin protein lack T cells and fail to respond to treatment while tumors with normal beta-catenin do.

Her lab focuses on understanding lung and pancreatic cancers, employing a multidisciplinary research team with expertise ranging from immunology and biology to math and computation. One of her graduate students is using linear algebra to develop a mathematical model for translating mouse data into more accurate predictions about key signaling pathways in humans.

Another project involves exploring the relationship between homogenous tumors and immune response. Not every cancer cell is identical, nor does it have the same molecules on its surface that can be recognized by an immune cell; cancer patients with a more homogenous expression of those cells do better with immunotherapy. To investigate whether that homogeneity is due to the tumor or to the immune response to the tumor, Spranger is seeking to build a model system. The research involves a lot of costly sequencing—up to $3,000 per attempt, which is fairly expensive for a young lab—and each try has an element of what Spranger half-jokingly describes as “close your eyes and hope it worked.”

“Being able to generate preliminary proof of concept data for high-risk projects is of outstanding importance for any principal investigator,” she says. “However, it is particularly important to have freedom and flexibility early on.”

Boosting potential

Advancing cancer research and supporting the careers of promising faculty were the intentions of Linda Stern and her late husband Howard Stern ’53, SM ’54, whose gift has supported a series of biology professors since 1993. The first appointee to the chair was Tyler Jacks, now director of the Koch Institute.

Linda Stern says her husband, the cofounder and chairman of E-Z-EM, Inc., and a pioneer in the field of medical imaging, gave thoughtfully to many charitable causes. Yet MIT, where he earned undergraduate and graduate degrees in chemical engineering, had a special place in his heart.

“He was very involved and loved MIT,” says Stern, whose own career path included working as a private detective for 28 years. “He made wonderful contacts and got a wonderful education. He was a real heavy hitter when it came to defending the university.”

MIT’s continued excellence in a competitive environment depends on its ability to recognize and retain faculty, nurture careers, support students, and allow for the pursuit of novel ideas. Like the full professorships awarded to tenured faculty members, career development professorships such as the one endowed by the Sterns fund salary, benefits, and a scholarly allowance. These shorter-term (typically three-year) appointments, however, are specifically meant to accelerate the research and career progression of junior professors with exceptional potential.

“The professorship showed me that MIT as a community is invested and interested in fostering my career,” says Spranger. The discretionary funds she receives from the chair can cover, without need for an approval process, expenses that are not paid for by grants or that suddenly arise from a new idea or opportunity. They can keep projects running in tough times, fund travel to conferences, and purchase equipment. “It gives you a little more traction,” Spranger says. “It’s probably the best invested money because you have a lot of ideas you want to test, and at the same time, you are still checking the pulse of where the field might go and where you want to build your niche.”

Committed to service and science

When senior Julia Ginder isn’t investigating the mystery of her own allergies, she’s volunteering to help young people reach their goals.

Gina Vitale | MIT News correspondent
February 25, 2019

Julia Ginder has to avoid a lot of foods due to allergies. From a young age, she got used to bringing her own snacks to birthday parties and group outings. But she didn’t really know the science behind her allergies until high school, when she read a chapter for class on immunology.

“I read it, and then I read it again, and I went running downstairs to tell my mom, ‘This is what’s wrong with me!’” she recalls.

From them on, Ginder was driven to learn about what made her body react so severely to certain stimuli. Now a biology major, she does research in the lab of Christopher Love, in the Koch Institute for Integrative Cancer Research, where she studies peanut allergies — one of the few food allergies she actually doesn’t have.

“I really enjoy figuring out, what’s the perspective from the biology side? What is the contributing chemistry? And how do those fit together?” she says. “And then, when you take a step back, how do you use that knowledge and perhaps the technology that comes out of it, and actually apply that in the real world?”

Nuts about research

In the Love lab, researchers look at how individual immune cells from people with peanut allergies react when stimulated with peanut extracts. More recently, they’ve been analyzing how the stimulated cells change over the course of treatment, evolving from one state to the next.

“You can watch the activation signals change over time in individual cells from peanut-allergic patients compared to healthy ones,” Ginder explains. “You can then dig deeper and look at distinct populations of cells at a single time point. With all of this information, you can start to get a sense of what critical cell types and signals are making the allergic person maintain a reaction.”

The researchers aim to figure out which cell types are associated with the development of tolerance so that more effective treatments can be developed. For instance, allergic people are sometimes given peanuts in small doses as a sort of biological exposure therapy, but perhaps if more key cell states are identified, targeted drug treatments can be added on top of that to induce those cell states.

Further pursuing her interest in health, Ginder spent the Independent Activities Period of her sophomore year volunteering for Boston Medical Center. The program she worked for helped families learn how to be advocates for their children with autism. For instance, it provided guidance on how to negotiate an appropriate accommodations agreement with their child’s school for their individual needs.

“It [the BMC experience] made it clear to me that for a child to succeed, they need to have support from both the educational side and the health side,” she says. “And it might seem obvious, but, especially for a child who might be coming from a less privileged background, those are two really important angles for ensuring that they are given the opportunity to reach their full potential.”

“The most helpful thing you can do is simply be there.”

Ginder became a swim coach and tutor for Amphibious Achievement in the fall of her first year, almost immediately after arriving at MIT. It’s a program that aims to help high schoolers reach both their athletic and academic goals. The high schoolers, often known as Achievers, are assigned a mentor like Ginder who helps with the academic and the athletic activities.

Local students come to MIT early Sunday morning to practice swimming or rowing, head to the Maseeh dining hall for lunch, participate in an afternoon academics lesson, reflect on their goals, and then spend a half an hour one-on-one with their mentor. It’s a big commitment for both the Achievers and mentors to spend almost six hours every Sunday with the program, but Ginder, who completed her two-year term as one of the co-executive directors this fall, has seen the importance of showing up week after week.

“The most helpful thing you can do is simply be there. Listen if they want to tell you anything, but really just being consistent — every single Sunday, being there.”

Ginder played on the field hockey team during her first year. However, when a practice during her sophomore year left her with a concussion and unable to play, she used the newfound spare time to start volunteering for Camp Kesem (CK). Having really enjoyed her experience at Amphibious Achievement, she was eager to be a counselor for the camp, which serves children whose parents are affected by cancer.

“Being there for someone, whether they are having a tough time or a great day, is really important to me. I felt that CK really aligned with that value I hold, and I hoped to meet even more people at MIT who felt that way. And so I joined, and I’ve loved it,” she says.

Management and moving west

Eventually, Ginder would like to become a physician, possibly in the fields of pediatrics and allergies. However, with a minor in public policy, she’s interested in developing areas outside of science as well. So, for the next couple of years, she’ll be moving westward to work as an associate consultant for Bain and Company in San Francisco.

“The reason I’m most interested in consulting is that there is this strong culture of learning and feedback. I want to improve my ability to be a strong team member, leader, and persuader. I think these are areas where I can continue to grow a lot,” she says. “It may sound silly, but I think for me, as someone who is 5’2” and hoping to become a pediatrician, it’s important to cultivate those professional skills early. I want to also serve as a leader and advocate outside of the clinic.”

As Ginder admits, the move is quite the geographic leap. Right now, her entire family is between a 20-minute and two-hour drive away. Moving to the opposite side of the country will be difficult, but she isn’t one to shy away from a challenge.

“I think it’ll be a bit sad because I’m not going to be as close to my family, but I think that it’ll really push me to be as independent as possible. I’ll need to look for my own opportunities, meet new people, build my network, and be my own person,” she says. “I’m really excited about that.”

From microfluidics to metastasis

New platform enables longitudinal studies of circulating tumor cells in mouse models of cancer.

Bendta Schroeder | Koch Institute
January 23, 2019

Circulating tumor cells (CTCs) — an intermediate form of cancer cell between a primary and metastatic tumor cell — carry a treasure trove of information that is critical to treating cancer. Numerous engineering advancements over the years have made it possible to extract cells via liquid biopsy and analyze them to monitor an individual patient’s response to treatment and predict relapse.

Thanks to significant progress toward creating genetically engineered mouse models, liquid biopsies hold great promise for the lab as well. These mouse models mimic many aspects of human tumor development and have enabled informative studies that cannot be performed in patients. For example, these models can be used to trace the evolution of cells from initial mutation to eventual metastasis, a process in which CTCs play a critical role. But since it has not been possible to monitor CTCs over time in mice, scientists’ ability to study important features of metastasis has been limited.

The challenge lies in capturing enough cells to conduct such longitudinal studies. Although primary tumors shed CTCs constantly, the density of CTCs in blood is very low — fewer than 100 CTCs per milliliter. For human patients undergoing liquid biopsy, this does not present a problem. Clinicians can withdraw enough blood to guarantee a sufficient sample of CTCs, just a few milliliters out of five or so liters on average, with minimal impact to the patient.

A mouse, on the other hand, only has about 1.5 milliliters of blood in total. If researchers want to study CTCs over time, they may safely withdraw no more than a few microliters of blood from a mouse each day — nowhere near enough to ensure that many (or any) CTCs are collected.

But with a new approach developed by researchers at the Koch Institute for Integrative Cancer Research, it is now possible to collect CTCs from mice over days and even weeks, and analyze them as the disease progresses. The system, described in the Proceedings of the National Academy of Sciences the week of Jan. 21, diverts blood to a microfluidic cell-sorting chip that extracts individual CTCs before returning the blood back to an awake mouse.

A menu of sorts

The inspiration for the project was cooked up, not in the lab, but during a chance encounter in the Koch Café between Tyler Jacks, director of the Koch Institute and the David H. Koch Professor of Biology, and Scott Manalis, the Andrew and Erna Viterbi Professor in the departments of Biological Engineering and Mechanical Engineering and a member of the Koch Institute.

As luck and lunch lines would have it, the pair would discuss thesis work being done by then-graduate student Shawn Davidson, who was using a dialysis-like system to track metabolites in the bloodstream of mice in the laboratory of Matthew Vander Heiden, an associate professor of biology. Jacks and Manalis were inspired: Could a similar approach could be used to study rare CTCs in real time?

Along with their Koch Institute colleague Alex K. Shalek, the Pfizer-Laubach Career Development Assistant Professor of Chemistry and a core member of the Institute for Medical Engineering and Science (IMES) at MIT, it would take Jacks and Manalis more than five years to put all the pieces of the system together, drawing from different areas of expertise around the Koch Institute. The Jacks lab supplied its fluorescent small cell lung cancer model, the Manalis lab developed the real-time CTC isolation platform, and the Shalek lab provided genomic profiles of the collected CTCs using single-cell RNA sequencing.

“This is a project that could not have succeeded without a sustained effort from several labs with very different sets of expertise. For my lab, which primarily consists of engineers, the opportunity to participate in this type of research has been incredibly exciting and is the reason why we are in the Koch Institute,” Manalis says.

The CTC sorter uses laser excitation to identify tumor cells expressing a fluorescent marker that is incorporated in the mouse model. The system draws blood from the mouse and passes it through a microfluidic chip to detect and extract the fluorescing CTCs before returning the blood back to the mouse. A minute amount of blood — approximately 100 nanoliters — is diverted with every detected CTC into a collection tube, which then is purified further to extract individual CTCs from the thousands of other blood cells.

“The real-time detection of CTCs happens at a flow rate of approximately 2 milliliters per hour which allows us to scan nearly the entire blood volume of an awake and moving mouse within an hour,” says Bashar Hamza, a graduate student in the Manalis lab and one of the lead authors on the paper.

Biology in their blood

With the development of a real-time cell sorter, the researchers could now, for the first time, longitudinally collect CTCs from the same mouse.

Previously, the low blood volume of mice and the rarity of CTCs meant that groups of mice had to be sacrificed at successive times so that their CTCs could be pooled. However, CTCs from different mice often have significantly different gene expression profiles that can obscure subtle changes that occur from the evolution of the tumor or a perturbation such as a drug.

To demonstrate that their cell-sorter could capture these differences, the researchers treated mice with a compound called JQ1, which is known to inhibit the proliferation of cancer cells and perturb gene expression. CTCs were collected and profiled with single-cell RNA sequencing for two hours prior to the treatment, and then every 24 hours after the initial treatment for four days.

When the researchers pooled data for all mice that had been treated with JQ1, they found that the data clustered based on individual mice, offering no confirmation that the drug affects CTC gene expression over time. However, when the researchers analyzed single-mouse data, they observed gene expression shift with time.

“What’s so exciting about this platform and our approach is that we finally have the opportunity to comprehensively study longitudinal CTC responses without worrying about the potentially confounding effects of mouse-to-mouse variability. I, for one, can’t wait to see what we will be able to learn as we profile more CTCs, and their matched primary and metastatic tumors,” says Shalek.

Researchers believe their approach, which they intend to use in additional cancer types including non-small cell lung, pancreatic, and breast cancer, could open new avenues of inquiry in the study of CTCs, such as studying long-term drug responses, characterizing their relationship to metastatic tumors, and measuring their rate of production in short timeframes — and the entire metastatic cascade. In future work, researchers also plan to use their approach for profiling rare immune cells and monitoring cells in dynamic contexts such as wound healing and tumor formation.

“The ability to study CTCs as well other rare cells in the blood longitudinally gives us a powerful view into cancer development. This sorter represents a real breakthrough for the field and it is a great example of the Koch Institute in action,” says Jacks.

The paper’s other co-lead authors are graduate students Sheng Rong Ng from the Jacks lab and Sanjay Prakadan from the Shalek lab. The research is supported, in part, by the Ludwig Center at MIT, the National Cancer Institute, the National Institutes of Health and the Searle Scholars Program.

Immune cell variations contribute to malaria severity

Natural killer cells’ failure to respond to infection may explain why the disease is more grave in some patients.

Anne Trafton | MIT News Office
October 4, 2018

At least 250 million people are infected with malaria every year, and about half a million of those die from the disease. A new study from MIT offers a possible explanation for why some people are more likely to experience a more severe, and potentially fatal, form of the disease.

The researchers found that in some patients, immune cells called natural killer cells (NK cells) fail to turn on the genes necessary to effectively destroy malaria-infected red blood cells.

The researchers also showed that they could stimulate NK cells to do a better job of killing infected red blood cells grown in a lab dish. This suggests a possible approach for developing treatments that could help reduce the severity of malaria infections in some people, especially children, says Jianzhu Chen, one of the study’s senior authors.

“This is one approach to that problem,” says Chen, an MIT professor of biology and a member of MIT’s Koch Institute for Integrative Cancer Research. “Most of the malaria patients who die are children under the age of 5, and their immune system has not completely formed yet.”

Peter Preiser, a professor at Nanyang Technical University (NTU) in Singapore, is also a senior author of the study, which appears in the journal PLOS Pathogens on Oct. 4. The paper’s lead authors are NTU and Singapore-MIT Alliance for Research and Technology (SMART) graduate students Weijian Ye and Marvin Chew.

First line of defense

In 2010, Chen and his colleagues engineered strains of mice that produce several types of human immune cells and red blood cells. These “humanized” mice can be used to study the human immune response to pathogens that don’t normally infect mice, such as Plasmodium falciparum, the parasite that causes malaria.

A few years later, the researchers used those mice to investigate the roles of NK cells and macrophages in malaria infection. These two cell types are key players in the innate immune system, a nonspecific response that acts as the first line of defense against many microbes. Chen and his colleagues found that when they removed human NK cells from the mice and infected them with malaria, the quantity of parasites in the blood was much greater than in mice with NK cells. This did not happen when they removed human macrophages, suggesting that NK cells are the most important first-line defenders against malaria.

A natural killer (NK) cell binds to a malaria-infected red blood cell and destroys it. Credit: Weijian Ye

In that study, the researchers also found that in about 25 percent of the human blood samples they used, the NK cells did not respond to malaria at all. In the new paper, they set out to try to find out why that was the case. To do that, they sequenced the RNA of NK cells before and after they encountered malaria-infected red blood cells. This allowed the researchers to identify a small number of genes that get turned on in malaria-responsive NK cells but not in nonresponsive cells.

Among these genes was one that codes for a protein called MDA5, which was already known to be involved in helping immune cells such as NK cells and macrophages recognize foreign RNA. Further studies revealed that malaria-infected red blood cells secrete tiny bubbles called microvesicles that carry pieces of RNA from the malaria parasite. The studies also showed that NK cells absorb these microvesicles. If MDA5 is present, the NK cell is activated to kill the infected blood cell.

Nonresponsive NK cells, which have lower levels of MDA5, fail to recognize and kill the infected cells. NK cells are also responsible for secreting cytokines that summon T cells and other immune cells, so their failure to activate also hinders other elements of the immune response.

Boosting immunity

Chen and his colleagues also showed that they could activate the nonresponsive NK cells by treating them with a synthetic molecule called poly I:C, which is structurally similar to double-stranded RNA. For poly I:C to be effective, the researchers had to package it into tiny spheres called liposomes, which allow it to enter cells just like the RNA-carrying microvesicles do.

The researchers also found a correlation between the levels of MDA5 in the NK cells and the disease severity experienced by the patients who donated the blood samples. Next, they hope to take cells from human patients and use them to further examine this correlation in humanized mice, and also to explore whether treating the mice with poly I:C would have the same beneficial effect they saw in cells grown in a lab dish.

The research was funded by the National Research Foundation of Singapore through the SMART Interdisciplinary Research Group in Infectious Disease Research Program.