“I never forget a face, but in your case I’ll make an exception.”

Groucho Marx, who immortalized that stand-up one-liner, might have been talking about the innate immunity phase of the human immune system. Innate immunity is the SWAT team that engages the pathogenic enemy well in advance of the classic adaptive immune system.

Immunologist Norman Letvin, at Harvard-affiliated Beth Israel Deaconess Medical Center in Boston, explained: “When battling infectious agents viruses, bacteria, fungi and all other pathogens the immune system relies on two separate types of immune responses: innate immunity and adaptive, or acquired, immunity. T cells with innate immunity function as the immune system’s first line of defense against foreign microbes. They kick in within hours of infection and temporarily stun the microbes into submission. Giving a small population of gamma-delta T cells a mnemonic taste of the TB bug may help protect the body against that disease.

“We assume,” Letvin continued, “that two waves of immune responses are involved in controlling an infection. The first wave that innate immune response covers a variety of immunological mechanisms that can partially contain or control the spread of an infectious agent. However, what sets innate immunity apart from the rest of the immune system is that the innate reaction does not recognize a specific antigen in or on its target pathogen. Also, it has no memory associated with that target.

“The second wave,” Letvin continued, “is an antigen-specific adaptive immune response. As opposed to innate immunity, the slower adaptive phase, which takes days or weeks to mature, specifically recognizes and memorizes the pathogen’s flag antigen. It will remember that the pathogen had been seen by the memory system before, and if it’s seen again, the immune system will ramp up very dramatically and rapidly, probably doing a better job of containing the infection.”

Letvin is corresponding author of a paper in Science, dated March 22, 2002, and titled: “Adaptive immune response of Vg2Vd2+ T cells during mycobacterial infections.” Its senior author is veteran tuberculosis researcher Zheng Chen, also at Beth Israel.

Upset Dogma Sets Up TB Vaccine Quest

“Our overall findings,” Letvin told BioWorld Today, “will likely have an important bearing on our understanding of how tuberculosis is controlled by the immune system and perhaps even how to approach making a vaccine to prevent TB infections.

“Tuberculosis,” he pointed out, “is a highly contagious bacterial infection that primarily attacks the lungs. The pathogen Mycobacterium tuberculosis is responsible for 2 million deaths each year, and infects an estimated 16 million people around the world. TB is a huge killer internationally,” Letvin went on. “Worldwide, the major targets for vaccine development are the HIV virus, the malarial parasite and M. tuberculosis. So anything that moves us a little closer to designing those vaccines is very important.”

Letvin noted, “The only existing vaccine against tuberculosis is BCG short for bacille Calmette-Guérin. It’s given to immunize children, but is so marginally effective that it’s not even used in the U.S. We need to have a fully effective vaccine, and the implications of this Science paper are important as we work toward that goal.”

The co-authors inoculated macaque monkeys the closest animal model to humans with the BCG vaccine, then after a brief interval, gave the animals a booster shot. As early as four to six days following this second inoculation, the team saw in the blood of the monkeys a marked expansion of those innate gamma-delta T cells. There was a pulmonary response as well. Lymphocyte populations demonstrated that the same reactions were seen systemically in the lungs which is where TB strikes. Finally, the authors challenged selected cohorts of these macaques the ones that already had been immunized before with BCG and na ve monkeys, with virulent M. tuberculosis aerosols. The latter group contracted severe TB infection and died. This was not surprising, as monkeys are extremely sensitive to tuberculosis infections.

“The Science study shows for the first time,” Letvin observed, “that this population of gamma-delta T cells straddles the boundaries between innate and more mature immunity, and implicates those T cells as at least one of the major players immunologically in containing tuberculosis infection. The Science paper reports,” Letvin noted, “that not only does a certain subpopulation of gamma-delta T cells identified as V-gamma-2 and V-delta-2 have in fact immunologic memory of a previous exposure to mycobacteria, but this innate immune response can be rapidly mobilized on repeated exposure of the immune system to the pathogen. This finding,” he observed, “blurs the line for the first time between innate immunity and more traditional or better-understood memory function. It shows that the mycobacteria that cause tuberculosis may well be controlled to a substantial extent by this in-between cell population.”

HIV Epidemic Complements TB Upsurge

“TB is a bigger problem in the U.S. today than it was in the past,” Letvin allowed, “because of people who are HIV-infected. Individuals, and the tuberculosis organism that they contract, can be resistant to the usual TB medications. So TB is a bigger headache to the treating physicians.

“We are proceeding with the design and construction of an effective vaccine,” he said. “Our laboratory has been involved to a great extent in the HIV vaccine arena. TB is really an overlapping problem with HIV. So we’re putting effort into this area as well.”

Letvin conceptualized the kind of anti-TB vaccine the lab is aiming at: “The traditional memory T-cell population recognizes protein antigen. The novel gamma-delta T cells, and their V subunits, appear to recognize an unusual lipid antigen. The most important lipid antigens comprise components of the mycobacterial TB organism wall. We have to consider using these lipid antigens in our approaches for making TB vaccines. We have to figure out ways of fabricating, purifying and delivering these kinds of lipids in a highly immunogenic form. This will be a challenge because no one’s ever done work of this type before. We have to do more basic science, then try to translate these observations into vaccine development. Research,” Letvin concluded, “is a much slower process than we’d like it to be.”