The 1980s was a heady time for T cell immunology at the US National Institutes of Health, with pioneering research leading to the cloning of the T cell receptor and the elucidation of MHC restriction, thymic selection and T cell subset differentiation. I was studying immune tolerance, trying to figure out how T cells are regulated, but the field was on the ropes. The two main concepts — the idiotype network and CD8+ T suppressor cells — had been discredited. Then one day I heard Marc Jenkins, a post-doc in Ron Schwartz’s lab, talk about an in vitro model of T cell suppression he was developing by exposing T cell clones to antigen-pulsed spleen cells (known as fixed antigen-presenting cells (APCs)), a method he had used during his graduate training to induce a profound state of tolerance in vivo.
The hope was that T cell clones stimulated by fixed APCs would convert into suppressor cells. The model didn’t work as the stimulated T cells were totally unresponsive, not immunosuppressive, but this failed experiment changed my view of T cell activation. The exposure to antigen was not inert, as the size of T cells was shown to increase (Marc was fastidious in looking at the cells through a microscope). In response to antigen recognition, the cells had become ‘anergic’ — shut down by the lack of a co-stimulatory or ‘second signal’ required for full activation.
This discovery changed the field and, for me, it was an epiphany that altered my thoughts about T cell tolerance. It seemed simple — all one needed to induce tolerance was to identify the second signal, develop a drug that blocked that signal and test the ability to induce tolerance in vivo! A concerted, multi-lab effort led to the identification of CD28–B7 interaction as the key second signal (reviewed by June et al., 1994). Cytotoxic T lymphocyte antigen 4 (CTLA4)–Ig was developed as a potent CD28 antagonist (Linsley et al., 1991). This allowed us to show that co-stimulation blockade could lead to robust, antigen-specific and permanent tolerance in mice (Lenschow et al., 1992).
Ultimately, these key discoveries led to approved drugs for the treatment of autoimmune disease and organ transplantation and to the discovery of CTLA4 as the first of many cell surface molecules that turn off activated T cells, giving birth to the field of checkpoint inhibition for the treatment of cancer. Science is a team sport but Marc’s contribution was a game changer for the field of T cell immunology and for me personally.
References
Original article
Jenkins, M. K. & Schwartz, R. H. Antigen presentation by chemically modified splenocytes induces antigen-specific T cell unresponsiveness in vitro and in vivo. J. Exp. Med. 165, 302–319 (1987)
Further reading
June, C. H. et al. The B7 and CD28 receptor families. Immunol. Today 15, 321–331 (1994)
Linsley, P. S. et al. CTLA-4 is a second receptor for the B cell activation antigen B7. J. Exp. Med. 174, 561–569 (1991)
Lenschow, D. J. et al. Long-term survival of xenogeneic pancreatic islet grafts induced by CTLA4Ig. Science 257, 789–792 (1992)
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Bluestone, J.A. Chance favours the prepared mind. Nat Rev Immunol 18, 541 (2018). https://doi.org/10.1038/s41577-018-0043-1
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DOI: https://doi.org/10.1038/s41577-018-0043-1