To many undergraduates, intermediary metabolism means late nights in the library, eyes glazed while trying to memorize the intricacies before the next morning’s exam. To Philippa Marrack, these biochemical pathways meant a gratifying cerebral jolt. Suddenly she understood how the body extracts energy from the food we eat.

When these processes hooked her in the mid 1960s, Marrack was studying science and mathematics at Cambridge University. She stayed there for her Ph.D. and joined a lab
that investigated what would be named T cells. The subject matter didn’t yet compel her: These immune cells had been discovered only a few years earlier, so no one knew whether they’d do anything interesting. Rather, she made the thesis choice because her advisor worked at an exciting place. The scintillating intellectual environment of the U.K.’s biochemical hub, the Medical Research Council’s Laboratory of Molecular Biology, seduced her.

In the early 1970s as a postdoc, Marrack met John Kappler, who would become her husband and scientific partner. By the decade’s end, immunologists had realized that T cells recognize chunks of foreign proteins—or antigens—only if they simultaneously detect particular host cell-surface proteins that display the antigen. No one knew, however, whether each T cell carries two receptor molecules—one that binds each of these components—or whether a single receptor attaches to both elements. Resolution of this issue was crucial if scientists wanted to understand how T cells identify the microbial antigens that provoke them to do battle.

Marrack and Kappler tackled this question by fusing cells that sense different antigen/host-protein pairs. If two separate receptors join forces, the receptors would re-assort and the merged cells would respond to new antigen/host-protein combinations.
Such novel reactivity did not materialize, indicating that a single T-cell receptor “sees” both molecules. The insight fueled an intense hunt for the receptor, which Marrack and
Kappler found in 1983 (concurrently with two other groups).

Four years later, Marrack’s team produced the first direct evidence to explain how our immune systems accomplish an astounding feat of molecular discrimination. Somehow our bodies get rid of T cells that attack our own tissues, yet retain those that combat invaders.

Normally, only a few mature T cells respond to any particular trigger. In certain mice, Marrack noticed, a huge number of these cells stirred when they encountered a specific unfamiliar protein. She analyzed T cells from different mice—those that harbored the same protein while T cells developed in the thymus. A dramatic result emerged: Mature T cells that perceive the protein were missing. This observation supported the notion that T cells encounter material from the body while they’re developing; if they bind it strongly, they are obliterated. Self-reactive T cells don’t escape the thymus alive and therefore don’t damage tissues.

This work on immunological tolerance laid the foundation for Marrack’s subsequent discovery of so-called microbial “superantigens,” which can stimulate rampant T-cell proliferation and a devastating inflammatory response. These molecules underlie scourges that include food poisoning and toxic shock syndrome.

Marrack’s pivotal work continues to provide key knowledge about how T cells—lynchpins of the immune system—fight germs, foster vaccine effectiveness, and misbehave in autoimmune diseases.

Author: Evelyn Strauss, Ph.D.