Becoming aware of gamma delta T cells

The discovery that B cells and alpha beta T cells exist was predictable: These cells gave themselves away through their products and biological effects. In contrast, there was no reason to anticipate the existence of gamma delta T cells. Even the accidental discovery of a novel TCR-like gene (later named gamma) that did not encode TCR alpha or beta proteins did not immediately change this. TCR-like gamma had no obvious function, and its early expression in the thymus encouraged speculation about a possible role in alpha beta T cell development. However, the identification of human PBL-derived cell-lines which expressed CD3 in complex with the TCR-like gamma protein, but not the alpha beta TCR, first indicated that a second T cell-type might exist, and the TCR-like gamma chain was observed to co-precipitate with another protein. Amid speculation about a possible second TCR, this potential dimeric partner was named delta. To determine if the delta protein was indeed TCR-like, we undertook to sequence it. Meanwhile, a fourth TCR-like gene was discovered and provisionally named x. TCR-like x had revealed itself through genomic rearrangements early in T cell development, and was an attractive candidate for the gene encoding delta. The observation that delta protein sequences matched the predicted amino acid sequences encoded by the x gene, as well as serological cross-reactivity, confirmed that the TCR-like x gene indeed encoded the delta protein. Thus, the gamma delta heterodimer was established as a second TCR, and the cells that express it (the gamma delta T cells) consequently represented a third lymphocyte-population with the potential of recognizing diverse antigens. Soon, it became clear that gamma delta T cells are widely distributed and conserved among the vertebrate species, implying biological importance. Consistently, early functional studies revealed their roles in host resistance to pathogens, tissue repair, immune regulation, metabolism, organ physiology and more. Albeit discovered late, gamma delta T cells have repeatedly proven to play a distinct and often critical immunological role, and now generate much interest.