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Unformatted text preview: NATURE MEDICINE VOLUME 13 | NUMBER 2 | FEBRUARY 2007 139 A brief history of T H 17, the first major revision in the T H 1/T H 2 hypothesis of T cellmediated tissue damage Lawrence Steinman For over 35 years, immunologists have divided T-helper (T H ) cells into functional subsets. T-helper type 1 (T H 1) cellslong thought to mediate tissue damagemight be involved in the initiation of damage, but they do not sustain or play a decisive role in many commonly studied models of autoimmunity, allergy and microbial immunity. A major role for the cytokine interleukin-17 (IL-17) has now been described in various models of immune-mediated tissue injury, including organ-specific autoimmunity in the brain, heart, synovium and intestines, allergic disorders of the lung and skin, and microbial infections of the intestines and the nervous system. A pathway named T H 17 is now credited for causing and sustaining tissue damage in these diverse situations. The T H 1 pathway antagonizes the T H 17 pathway in an intricate fashion. The evolution of our understanding of the T H 17 pathway illuminates a shift in immunologists perspectives regarding the basis of tissue damage, where for over 20 years the role of T H 1 cells was considered paramount. The T H 1/T H 2 hypothesis was developed out of an attempt to answer two major questions that immunologists confronted in the mid 1980s: (i) was there a distinct T H subset that mediated delayed-type hypersen- sitivity, whereby T H cells damage tissues, and (ii) was there another T H subset that provided help for B cells, leading to antibody production 13 ? The answers to these questions, posed by Robert Coffman and Tim Mosmann 20 years ago, made a startling impact on how immunologists viewed the world of inflammation. They showed that so-called type 1 CD4 T-helper cells (T H 1) drive cell-mediated immune responses lead- ing to tissue damage, and they learned that these T H 1 cells also drive antibody-mediated responses in certain subclasses of the G isotype of immunoglobulin (Ig) antibody, specifically termed IgG 2a . In con- trast, type 2 CD4 T-helper cells (T H 2) drive certain antibody-mediated responses, particularly those that are involved in allergy dominated by the IgE isotype 3 . Like all hypotheses, there were certain phenomena, particularly in the area of T cellmediated tissue damage, that could not be explained by T H 1 and T H 2 and where the predictions of the hypothesis stood in stark contrast to the experimental data. Nevertheless, given our primitive state of knowledge about cytokines at that time, compared to our current level of understanding, the T H 1/T H 2 hypoth- esis had remarkable durability, despite its flaws and blemishes. Most importantly, it gave to us immunologists the notion that whole sets of T cells could reciprocally inhibit the functions of other sets of T cells: cytokines produced by T H 1 cells could negatively regulate the function of T H 2 cells and vice versa 13 ....
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This note was uploaded on 01/03/2012 for the course BI 144 taught by Professor List during the Fall '10 term at Caltech.
- Fall '10