Study Re-maps T Cell Homing, May Redirect Vaccine Development Strategies

The cellular immune system may remember not only what pathogens have invaded the body, but also the route by which they gained entry, according to a study published in the September Immunity.

While researchers have long understood that the movement of activated T cells from one organ to another is highly regulated, the mechanisms that guide this process, known as T cell homing, have remained unclear. In shedding light on the subject, Thomas Kupper and his colleagues have presented results that challenge several previous studies on T cell homing. The researchers hope the new findings will facilitate the development of more effective vaccines.

After a localized infection, memory CD8+ T cells can be found throughout the secondary lymphatic system, in lymph nodes far removed from the initial site of infection. According to the current paradigm, chemokine receptors on the surface of the cells guide them through secondary lymphoid organs to the corresponding adhesion molecules of infected tissue. But how each activated T cell comes to express its particular brand of receptor—called its homing imprint—and how some cells end up in distant lymph nodes are still a mystery.

To examine this phenomenon, Kupper, the Thomas B. Fitzpatrick professor of dermatology at HMS and Brigham and Women’s Hospital, and Luzheng Liu, HMS instructor in dermatology, compared the traffic patterns and tissue-homing phenotypes of CD8+ T cells in mice that had been inoculated with live vaccinia virus either cutaneously or via intraperitoneal injection. They found that at first T cells were primarily activated in the lymph nodes draining the infected tissue. These activated cells were then imprinted with the corresponding homing phenotype: skin-homing for cutaneously inoculated mice and gut-homing for those that received intraperitoneal injections. But not all of the cells migrated to the infected tissue. Within five days of inoculation, some activated T cells had traveled to distant lymph nodes, where they acquired additional homing imprints. As the authors point out, this is the first study to find multiple homing phenotypes on activated T cells.

The number of activated T cells eventually reached equilibrium among all lymph nodes, suggesting a homeostatic control mechanism that maintains a balance of memory cells throughout the body. One caveat is that the researchers looked exclusively at memory cells in lymphoid tissue; further work is needed to determine whether this pattern is consistent for non--lymphoid tissue.

After the virus had been eliminated, the original homing imprint became the predominant phenotype on memory CD8+ T cells in all secondary lymphoid organs. According to the study, it is the specific lymph node where T cells are activated, not the route of infection that determines their homing imprint. All CD8+ memory T cells bear this homing imprint regardless of how far they migrate or by what route the pathogen was introduced.

This finding in particular has direct implications for vaccine development: vaccination strategies that focus on the tissues most likely to be the first infected by a given pathogen may provide the best protection.

—Jeneen Interlandi

Weight Gain Between Pregnancies Tied to Later Pregnancy Complications

Mothers who gain even modest amounts of weight between pregnancies face a higher risk of pregnancy complications such as gestational diabetes, macrosomia, and stillbirth, according to a study in the Sept. 30 Lancet.

While the relationship between obesity and adverse pregnancy outcomes has long been suspected, researchers have yet to establish whether one causes the other, or if both are engendered by a third undetermined factor. Eduardo Villamor, HSPH assistant professor of international nutrition, has addressed this question by measuring not just weight in expectant mothers, but weight change from the first pregnancy to the second. By demonstrating that risks are related to the change in weight over time, Villamor has strengthened the case for a cause-and-effect relationship.

In a study funded by the Karolinska Institute, Villamor and his colleagues compared the body mass index at the beginning of the first and second pregnancies for more than 150,000 women recorded on the Swedish Birth Register between 1992 and 2001. They found the risk of major perinatal complications was strongly related to the amount of weight gained between pregnancies, even for women who did not become overweight or obese. For some conditions, such as gestational hypertension and diabetes, this association was actually stronger in women who maintained a healthy BMI for both pregnancies than in women who were overweight or obese during the first pregnancy.

The group also reported a dose–response effect: the risk of suffering any one of several adverse pregnancy outcomes began to rise with just 3 to 6 kg of weight gain between pregnancies and increased progressively as the number of kilograms rose. The risk of stillbirth, for example, was 63 percent greater for women who gained 9 or more kilograms than for women who gained less than 1.

To ensure that measured effects were due to weight gain, the team adjusted for other known predictors of pregnancy complications, including maternal age and smoking. The use of standardized records and the relative homogeneity of the population were also believed to enhance the clarity of the results.

—Jeneen Interlandi

Speakers Weave Science of Social Connection

The 17th-century philosopher René Descartes proclaimed that it is only through the thinking mind that human beings can know the world. The emphasis on rational thought has echoed through the ages, nowhere more loudly than in science. Yet today scientists from a variety of disciplines are converging on an opposing argument—that it is through our emotional and social interactions with one another that human beings come to know their world.

“Being affected by others is a design feature of human beings,” said Bruce Reis, adjunct assistant professor of psychology at New York University. He was speaking at a symposium on “Shared Subjectivities in Brain, Mind, and Psychopathology,” held on Oct. 14 at Harvard University. The conference, organized by Jack Burke and colleagues in the Department of Psychiatry at the Cambridge Health Alliance in conjunction with the Tavistock Clinic in London, brought together researchers in neuroscience, psychopathology, and primatology to discuss the latest findings in what is being called the new science of social relatedness.

Jean Decety, a neuroscientist at the University of Chicago, told the audience of more than 200 that we are essentially wired to feel one another’s pain. He described how neurons in the anterior cingulate cortex become activated when we imagine ourselves or other people in pain. His experiments are helping to establish a biological basis for empathy.

Peter Hobson of University College, London, described how an infant’s attention is directed to objects in the world by a mother’s gaze and how our perception of objects in the world continues to depend on relationships to other people. “All this occurs prior to our cognitive understanding,” he said. People with autism often do not make eye contact. “They do not relate to the world through the other,” he said.

“Taking the role of the other could be based on the experience of being an object of attention for another,” said Karlen Lyons-Ruth, HMS associate professor of psychology in the Department of Psychiatry at Cambridge Hospital. She described how lack of attention by a mother due to her own attachment problems or similar deficiencies like those that may occur in an orphanage can create problems later in life.

According to Sarah Hrdy, professor emerita at the University of California, Davis, our evolutionary history may have made human mothers more susceptible to such attachment disorders. Women had to depend on other members of the group to raise their infant, which may have relaxed selective pressure for a strong maternal instinct while favoring a human infant’s ability to engage others. “From birth, the infant had to appeal to the mother whose commitment was more contingent,” she said.

As it turns out, Descartes’ mother died of TB soon after his birth, though not before passing it on to her son. “He was raised in solitude and in bed,” Reis said. “He may have taken his own autism as the natural state of man.

—Misia Landau

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