|For this article, Ricki Lewis interviewed Polly Matzinger, section head for T-cell tolerance and memory at the National Institute of Allergy and Infectious Diseases, William Heath, senior research fellow in the immunology division of the Walter and Eliza Hall Institute of Medical Research in Melbourne, and Stephen P. Schoenberger, assistant member in the division of immune regulation at the La Jolla Institute for Allergy and Immunology. Data from the Web of Science (ISI, Philadelphia) show that these papers have been cited 50 to 100 times more often than the average paper of the same type and age. |
J.P. Ridge, F. Di Rosa, and P. Matzinger, "A conditioned dendritic cell can be a temporal bridge between a CD4+ T-helper and a T-killer cell," Nature, 393:474-8, 1998. (Cited in more than 250 papers since publication)
S.R.M. Bennett, F.R. Carbone, F. Karamalis, R.A. Flavell, J.F.A.P. Miller, and W.R. Heath, "Help for cytotoxic-T-cell responses is mediated by CD40 signalling," Nature, 393:478-80, 1998. (Cited in more than 215 papers since publication)
S.P. Schoenberger, R.E.M. Toes, E.I.H. van der Voort, R. Offringa, and C.J.M. Melief, "T-cell help for cytotoxic T lymphocytes is mediated by CD40-CD40L interactions," Nature, 393:480-3, 1998. (Cited in more than 220 papers since publication)
"The idea that T help could be routed through the APC was first proposed by Polly Matzinger.1 Her model postulated that helper T cells would provide the APC with a signal leading to its activation and subsequent competence for CTL priming. These three papers identify CD40L and CD40 communicating this 'help' signal from the helper T cell to the APC. This simpler model also explains why the T requirement for CTL priming is conditional, not absolute; some pathogens and antigenic formulations are able to achieve the same functional activation of APCs as helper T cells do via CD40 ligation," explains Stephen P. Schoenberger, assistant member in the division of immune regulation at the La Jolla Institute for Allergy and Immunology and lead author of the third paper. However, Matzinger, section head for T-cell tolerance and memory at the National Institute of Allergy and Infectious Diseases, traces her vision of a helper T cell acting through an APC to Kevin Lafferty.2
Cell type frequencies led the researchers to the new view of helper-APC-killer cell choreography--specifically, the extreme rarity of the CD4+ helper and CD8+ killer T cells. Getting two to meet on the same APC, at the same time, sounded a little like asking two specific people in China to meet by chance. "It was suggested in 1982 that helpers and killers need to see the same cell,3 but it wasn't really presented as a frequency problem. We suggested that one way to fix that would be if the helper treats a dendritic cell [a type of APC] like it does a B cell, helping one cell, then another, then another," explains Matzinger. And the frequencies were almost unimaginably small. Adds Schoenberger, "If each type of T cell is present in the naïve population at a frequency of perhaps 1 in 100,000 to 1,000,000 cells, it seemed highly unlikely that both helper and killer would be in the same place at the same time. Polly's model makes more sense." The helper and killer were thought to bind simultaneously because of the presence of IL-2, which is soluble and therefore acts over a short distance, he adds.
Stephen P. Schoenberger
Another challenge of groundbreaking results is to adapt terminology. Matzinger's is vivid. The helper cell "engages and conditions" the dendritic cell, which as a result becomes "empowered" to stimulate a killer cell. But these weren't her first word choices. She had wanted to use the term "superactivated" to describe one of possibly several states of an APC cell. "A reviewer said 'super' is overused, and it should be reserved for laundry products. However, we were allowed to use 'conditioned.' I did get some flak over 'empowered,' but it stayed. And Antonio Lanzavecchia, in the accompanying News and Views,4 used 'licensed,'" she explains, adding that the import of an APC taking on different tasks in different situations may have been muddied in the inconsistent language. (Matzinger does get to choose names for her T-cell clones. Helper T-cell residents of her lab are from clones called Marilyn (for Monroe), Florence (for Nightingale), or Rachael, of biblical origin. Killers are from a Matahari clone, although Matzinger recently learned that Matahari did not, in fact, kill anyone.
From an applied standpoint, the revelation of APC conditioning suggests exciting potential for immune regulation. "It is gradually becoming appreciated that APCs have the capacity to inhibit, as well as activate, T-cell responses. These disparate functional outcomes may well depend on the conditioning signals that the APC receives during its maturation. In understanding how CD40 signaling modifies APC function, we can hopefully learn how to use this and other pathways to control T-cell responses. This would have broad applicability in cancer, infectious disease, and autoimmunity," says Schoenberger. "It may be possible to generate killer cell immunity in situations where helper cells are not available," such as in AIDS patients or tumors that squelch helper T-cell activation, Heath elaborates. "Alternatively, we may be able to block the induction of CTLs by blocking CD40/CD40L interaction in circumstances where killer cells cause problems, such as autoimmune diseases," he adds. Since publication of the three papers, others have indeed used CD40 antibodies as adjuvants in a variety of settings, Schoenberger points out. Most recently, for example, researchers at the Kennedy Institute of Rheumatology in London are using an anti-CD40 antibody that reduces joint inflammation in a mouse model of rheumatoid arthritis.5
Heath, Matzinger, and Schoenberger agree that the three papers have been heavily cited because they answer a question that has puzzled immunologists for years. "The work details one of the basic steps in the generation of killer cell immunity, which is important for many aspects of immunology, particularly vaccine development," Heath sums up. Adds Schoenberger, "The idea that an APC can possess different functional states of activation is intriguing, and brings the APC into focus as a central player in the regulation of immune responses. These three papers represent a cornerstone for this line of thinking."
Ricki Lewis (firstname.lastname@example.org) is a contributing editor for The Scientist.
1. S. Guerder, P.J. Matzinger, "A fail-safe mechanism for maintaining self-tolerance," Journal of Experimental Medicine, 176:553-64, 1992.
2. K.J. Lafferty, A.J. Cunningham, "A new analysis of allogeneic interactions," Australian Journal of Experimental Biology and Medical Science, 53:27-42, 1975.
3. J.A. Keene, J. Forman, "Helper activity is required for the in vivo generation of cytotoxic T lymphocytes," Journal of Experimental Medicine, 155:768-82, 1982.
4. A. Lanzavecchia, "Licence to kill," Nature, 393:413-4, June 4, 1998.
5. C. Mauri et al., "Therapeutic activity of agonistic monoclonal antibodies against CD40 in a chronic autoimmune inflammatory process," Nature Medicine, 6:673-9, June 2000.